1. 1 Cytologic Features of Urothelial Carcinoma in Catheterized Urine with Cellular Fragments 萬芳醫院 陳嘉偉 Mohamed El-Fakharany, M.D. et al. ACTA CYTOLOGICA May-June 2006

2. 2 Objective To identify architectural and cytomorphologic differences that might help distinguish urothelial neoplasms from instrumentation artifact

3. 3 Introduction (1) Powerful tools for screening bladder tumors is the urine cytology smear Several findings that can help the cytopathologist diagnose bladder neoplasms on these smears. Presence of cellular fragments in voided urine specimens, especially in patients with no history of renal stones, strongly raises the suspicion of a tissue-shedding bladder neoplasm.

4. 4 catheterized urine specimens, these tissue fragments usually present a challenge to the cytopathologist mechanical trauma (also known as instrumentation artifact) or due to a true bladder neoplasm (particularly low grade neoplasms). Introduction (2)

5. 5 Introduction (3) This instrumentation artifact can cause a rate of false positive diagnosis of urothelial neoplasms (e.g., urothelial carcinoma) as high as 11% ( Rife CC, et al,Urol Clin North Am 1979;6:599–612)

6. 6 Introduction (4) Study to identify the cytomorphologic differences between cellular fragments shed by bladder tumors and those shed by mechanical instrumentation trauma.

7. 7 Study Design Examined 73 cytologic smears of catheterized urine containing urothelial cell clusters - 1998 and 2004. All patients had at least 1 follow-up biopsy. Smears were reviewed for several morphologic features blindly, without knowledge of the follow-up diagnosis.

8. 8 Materials and Methods (1) 15,000 urine cytology smears - 1998 and 2004. Identified 73 smears of catheterized urine specimens diagnosis ( artifact vs. neoplasm ), and each had at least 1 follow-up urinary bladder biopsy for definitive diagnosis.

9. 9 Reviewed features: a thin rim of cytoplasm (collar) around cell fragments (present vs. absent) Fragment border (regular vs. irregular) Nuclear diameter Nuclear chromatin (fine vs. coarse) Nucleoli (prominent, present or not seen) Background inflammation (present vs. absent). Materials and Methods (2)

10. 10 The nuclear and fragment diameters were measured along the long axis using a calibrated eyepiece. Results were then analyzed (  2 test) against the follow-up diagnosis to determine which parameters were significant in distinguishing benign cell clusters from urothelial carcinoma Materials and Methods (3)

11. 11 Results 73 smears- 39 benign diagnosis 34 urothelial carcinoma on biopsy Review results: significant differences between benign and malignant cases with respect to 4 features: cytoplasmic collar, fragment border, nuclear chromatin and nuclear diameter.

12. 12 Results Fragment border (cytoplasmic collar) Benign cases 74% (29 of 39) Malignant cases 15% (5 of 34) (p < 0.0001) (Figure 1)

13. 13 Figure 1 Cytoplasmic collar.(A) Instrumentation artifact. (B)Urothelial carcinoma. AB

14. 14 Results Regular and rounded fragment borders Benign cases, 80% (31 of 39) malignant cases, 24% (8 of 34) Irregular and/or ragged fragment edges 76% ( 26 of 34) (p < 0.0001) (Figure 2)

15. 15 Figure 2 Fragment border.(A) Instrumentation artifact. (B)Urothelial carcinoma. AB

16. 16 Results Nuclear chromatin -fine and evenly dispersed Benign cases-64% (25 of 39) Malignant cases 18% (6 of 34); Nuclear chromatin -coarse and clumped Malignant cases 82% (p < 0.0001) (Figure 3)

17. 17 Figure 3 Nuclear chromatin.(A) Instrumentation artifact. (B)Urothelial carcinoma. AB

18. 18 Results Nuclear size Benign cases –12 μm Malignant cases – 16 μm Maximum nuclear diameter of 20 - 7 cases; proven malignant on follow-up biopsy (p < 0.0001) (Figure 4)

19. 19 Figure 4 Nuclear diameter.(A) Instrumentation artifact. (B)Urothelial carcinoma. AB

20. 20 Results ParameterArtifactNeoplasm Collar around cell fragmentsPresentAbsent Fragment borderRegularIrregular Nuclear chromatinFineCoarse Nuclear diameter >16 μm12 μm NucleoliPresent Present or not present Background inflammationPresentAbsent

21. 21 Discussion (1) Low grade bladder malignancy vs. catheterized urine specimens ( 0-73%) Lack of distinguish between cellular fragments due to true bladder neoplasms, mechanical trauma Rife CC, et al, Urol Clin North Am 1979 6. Koss LG, Dietch D, et al,Acta Cytol 1985 Shenoy UA, et al, Cancer 1985

22. 22 Discussion (2) Irregular,ragged border, absent cytoplasmic collar and coarse nuclear chromatin were combined, the sensitivity for diagnosing true malignant cellular fragments was 100% and the specificity, 94%. Nuclear diameter of ≥ 20 μm was 100% specific for malignancy

23. 23 Discussion (3) The concurrent presence of the above features is a powerful tool that should be used by the cytopathologist to screen out urothelial carcinoma in catheter urine cytology Avoid unnecessary follow-up procedures and help provide more efficient health care

24. 24 Conclusion Certain architectural and nuclear features can help differentiate urothelial neoplasms from instrumentation artifact in urine cytologic smears.

25. 25 Thanks for your attention