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Diagnostic Significance of Cytokeratin 20 and p53 as Adjunct Immunocytological Markers in Urine Cytology to Detect Urothelial Carcinomas: A Systematic Review Study

Document Type : Systematic Review

Author

Department of Pathology, Sree Mookambika Institute of Medical Sciences, Kulasekharam. The Tamilnadu Dr. M.G.R Medical University, India

Abstract

The progression and recurrence of urothelial carcinoma (UC) are correlated with carcinoma in situ and urothelial dysplasia. It is frequently challenging to distinguish dysplasia and carcinoma in situ from reactive atypia only based on histological characteristics. In daily practices, 2 of the adjunct immunohistochemistry markers (cytokeratin 20 (CK20) and p53) are used in addition to the histology to diagnose carcinoma in situ. This is accomplished by combining histological research results with immunohistochemistry. This systematic review summarizes the current findings on the diagnostic significance of p53 and CK20 as adjunct markers to urine cytology in the detection of UC. A systematic search of the relevant literature was conducted using PubMed, Wiley Online Library, and ScienceDirect databases. After screening for the eligibility criteria, a total of 14 selected articles were reviewed. Data extraction included a total number of samples, specimen samples, type of cells, and outcome parameters (mainly sensitivity and specificity). Urine cytology alone had a sensitivity of 75%-85% and specificity of 66%-95%. CK20 with urine cytology staining showed improved sensitivity and specificity in the range of 77%-94% and 71%-100%, respectively; p53 immunostaining with urine cytology showed a sensitivity of 52%-86% and specificity of 80%-98%. The dual staining in combination with urine cytology showed comparatively higher sensitivity and specificity in the range of 70%-90% and 74%-100%, respectively. This was more evident for high-grade UC (HGUC). Overall, single or dual staining combined with urine cytology was effective in this detection and can be applied as an adjunct marker in urine cytology.

Keywords

Main Subjects

References
  1. Wong-You-Cheong JJ, Woodward PJ, Manning MA, Sesterhenn IA. Neoplasms of the urinary bladder: radiologic-pathologic correlation. Radiographics. 2006;26(2):553-80. [DOI:10.1148/rg.262055172] [PMID]
  2. Akhtar M, Rashid S, Gashir MB, Taha NM, Al Bozom I. CK20 and CK5/6 immunohistochemical staining of urothelial neoplasms: A Perspective. Adv Urol. 2020;2020:e4920236. [DOI:10.1155/2020/4920236] [PMID] [PMCID]
  3. Bogen JP, Grzeschik J, Jakobsen J, Bähre A, Hock B, Kolmar H. Treating Bladder Cancer: Engineering of Current and Next Generation Antibody-, Fusion Protein-, mRNA-, Cell- and Viral-Based Therapeutics. Frontiers in Oncology [Internet]. 2021 [cited 2022 May 1];11. Available from: https://www.frontiersin.org/article/10.3389/fonc.2021.672262 [DOI:10.3389/fonc.2021.672262] [PMID] [PMCID]
  4. Calistri D, Casadio V, Bravaccini S, Zoli W, Amadori D. Urinary biomarkers of non-muscle-invasive bladder cancer: current status and future potential. Expert Review of Anticancer Therapy. 2012;12(6):743-52. [DOI:10.1586/era.12.50] [PMID]
  5. Barkan GA, Wojcik EM, Nayar R, Savic-Prince S, Quek ML, Kurtycz DF, Rosenthal DL. The Paris system for reporting urinary cytology: the quest to develop a standardized terminology. Acta Cytol. 2016;60(3):185-97. [DOI:10.1159/000446270] [PMID]
  6. Cheng L, Davidson DD, Maclennan GT, Williamson SR, Zhang S, Koch MO, et al. The origins of urothelial carcinoma. Expert Rev Anticancer Ther. 2010; 10(6):865-80. [DOI:10.1586/era.10.73] [PMID]
  7. Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet III GP, et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology. 2005;66(6):35-63. [DOI:10.1016/j.urology.2005.08.064] [PMID]
  8. Minasi S, Bosco D, Moretti B, Giangaspero F, Santoro A, Buttarelli FR. Improvement of the Collection, Maintenance, and Analysis of Neoplastic Cells from Urine Specimens with the Use of CytoMatrix. Methods Protoc. 2021;4(3):65. [DOI:10.3390/mps4030065] [PMID] [PMCID]
  9. Reid MD, Osunkoya AO, Siddiqui MT, Looney SW. Accuracy of grading of urothelial carcinoma on urine cytology: an analysis of interobserver and intraobserver agreement. Int J Clin Experimentalpathol. 2012;5(9):882.
  10. Sugeeta SS, Sharma A, Ng K, Nayak A, Vasdev N. Biomarkers in Bladder Cancer Surveillance. Frontiers in Surgery [Internet]. 2021 [cited 2022 May 1];8. Available from: https://www.frontiersin.org/article/10.3389/fsurg.2021.735868 [DOI:10.3389/fsurg.2021.735868] [PMID] [PMCID]
  11. Mallofré C, Castillo M, Morente V, Solé M. Immunohistochemical expression of CK20, p53, and Ki-67 as objective markers of urothelial dysplasia. Modernpathology. 2003;16(3):187-91. [DOI:10.1097/01.MP.0000056628.38714.5D] [PMID]
  12. Budman LI, Kassouf W, Steinberg JR. Biomarkers for detection and surveillance of bladder cancer. Canadian Urol Assoc J. 2008;2(3):212-21. [DOI:10.5489/cuaj.600] [PMID] [PMCID]
  13. Cina SJ, Lancaster-Weiss KJ, Lecksell K, Epstein JI. Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology classification system for urothelial neoplasia. Arch Pathol Lab Med. 2001;125(5):646-51. [DOI:10.5858/2001-125-0646-COKAPW] [PMID]
  14. Alsheikh A, Mohamedali Z, Jones E, Masterson J, Gilks CB. Comparison of the WHO/ISUP classification and cytokeratin 20 expression in predicting the behavior of low-grade papillary urothelial tumors. Mod Pathol. 2001 Apr;14(4):267-72. [DOI:10.1038/modpathol.3880300] [PMID]
  15. Jacob JT, Coulombe PA, Kwan R, Omary MB. Types I and II keratin intermediate filaments. Cold Spring Harbour perspectives inbiology. 2018;10(4):a018275. [PMID] [PMCID] [DOI:10.1101/cshperspect.a018275]
  16. Hong M, He G, Goh S, Low AW, Tay KJ, Lim TK, et al. Biomarkers for precision urothelial carcinoma diagnosis: Current approaches and the application of single-cell technologies. Cancers. 2021;13(2):E260. [DOI:10.3390/cancers13020260] [PMID] [PMCID]
  17. Desai S, Dug Lim S, Jimenez RE, Chun T, Keane TE, McKenney JK, et al. Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pTa and pT1 papillary urothelial neoplasia. Modern Pathology Off J U S Can Acad Pathol Inc. 2000;13(12):1315-23. [DOI:10.1038/modpathol.3880241] [PMID]
  18. Rotem D, Cassel A, Lindenfeld N, Mecz Y, Sova Y, Resnick M, et al. Urinary cytokeratin 20 as a marker for transitional cell carcinoma. Europeanurology. 2000;37(5):601-4. [DOI:10.1159/000020199] [PMID]
  19. Mi Y, Zhao Y, Shi F, Zhang M, Wang C, Liu X. Diagnostic accuracy of urine cytokeratin 20 for bladder cancer: A meta-analysis. Asia Pac J Clin Oncol. 2019;15(2):e11-9. [DOI:10.1111/ajco.13024] [PMID]
  20. Malats N, Bustos A, Nascimento CM, Fernandez F, Rivas M, Puente D, et al. P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol. 2005;6(9):678-86. [DOI:10.1016/S1470-2045(05)70315-6] [PMID]
  21. Hodgson A, Xu B, Downes MR. p53 immunohistochemistry in high-grade urothelial carcinoma of the bladder is prognostically significant. Histopathology. 2017;71(2):296-304. [DOI:10.1111/his.13225] [PMID]
  22. Enomoto K, Matsunaga T, Sofue T, Nakamura A, Hirakawa E, Ibuki E, et al. p53 expression in repair/reactive renal tubular cells: A potential pitfall leading to a false‐positive diagnosis of urine cytology. Cancer Medicine. 2021;10(24):8846-53. [DOI:10.1002/cam4.4389] [PMID] [PMCID]
  23. Wadhwa N, Diwaker P, Lotha N, Arora VK, Singh N. Cytokeratin 20 immunocytochemistry on urine sediments: a potential low-cost adjunct to cytology in the diagnosis of low-grade urothelial carcinoma. Cytopathol Off J Br Soc Clin Cytol. 2017;28(6): 531-5. [DOI:10.1111/cyt.12463] [PMID]
  24. Soyuer I, Sofikerim M, Tokat F, Soyuer S, Ozturk F. Which urine marker test provides more diagnostic value in conjunction with standard cytology- ImmunoCyt/uCyt+ or Cytokeratin 20 expression. Diagnosticpathology. 2009;4:20. [DOI:10.1186/1746-1596-4-20] [PMID] [PMCID]
  25. Melissourgos ND, Kastrinakis NG, Skolarikos A, Pappa M, Vassilakis G, Gorgoulis VG, et al. Cytokeratin-20 immunocytology in voided urine exhibits greater sensitivity and reliability than standard cytology in the diagnosis of transitional cell carcinoma of the bladder. Urology. 2005;66(3):536-41. [DOI:10.1016/j.urology.2005.04.022] [PMID]
  26. Srivastava R, Arora VK, Aggarwal S, Bhatia A, Singh N, Agrawal V. Cytokeratin-20 immunocytochemistry in voided urine cytology and its comparison with nuclear matrix protein-22 and urine cytology in the detection of urothelial carcinoma. Diagnosticcytopathol. 2012;40(9): 755-9. [DOI:10.1002/dc.21617] [PMID]
  27. Lin S, Hirschowitz SL, Williams C, Shintako P, Said J, Rao JY. Cytokeratin 20 as an immunocytochemical marker for detection of urothelial carcinoma in atypical cytology: preliminary retrospective study on archived urine slides. Cancer Detection and Prevention. 2001;25(2):202-9.
  28. Bhatia A, Dey P, Kumar Y, Gautam U, Kakkar N, Srinivasan R, et al. Expression of cytokeratin 20 in urine cytology smears: a potential marker for the detection of urothelial carcinoma. Cytopathology Off J Br Soc Clin Cytol. 2007;18(2):84-6. [DOI:10.1111/j.1365-2303.2006.00432.x] [PMID]
  29. Golijanin D, Shapiro A, Pode D. Immunostaining of cytokeratin 20 in cells from voided urine for detection of bladder cancer. The Journal of urology. 2000;164(6):1922-5. [DOI:10.1016/S0022-5347(05)66919-4] [PMID]
  30. Morsi MI, Youssef AI, Hassouna MEE, El-Sedafi AS, Ghazal AA, Zaher ER. Telomerase activity, cytokeratin 20 and cytokeratin 19 in urine cells of bladder cancer patients. J Egypt Natl Cancer Inst. 2006;18(1):82-93.
  31. Brisuda A, Háček J, Čechová M, Škapa P, Babjuk M. Diagnosis of urinary bladder urothelial carcinoma by immunocytology with p53, MCM5, MCM2 and Ki-67 antibodies using cell blocks derived from urine. Cytopathology Off J Br Soc Clin Cytol. 2019;30(5):510-8. [DOI:10.1111/cyt.12698] [PMID]
  32. Courtade-Saïdi M, Aziza J, d'Aure D, Bérard E, Evrard S, Basset C, et al. Immunocytochemical staining for p53 and Ki-67 helps to characterise urothelial cells in urine cytology. Cytopathol Off J Br Soc Clin Cytol. 2016;27(6):456-64. [DOI:10.1111/cyt.12332] [PMID]
  33. Arville B, O'Rourke E, Chung F, Amin M, Bose S. Evaluation of a triple combination of cytokeratin 20, p53 and CD44 for improving detection of urothelial carcinoma in urine cytology specimens. Cytojournal. 2013;10:25. [DOI:10.4103/1742-6413.123784] [PMID] [PMCID]
  34. Kim HJ, Yoo JH. Cytokeratin 20/p53 dual immunocytochemistry for improving the diagnostic accuracy of urine liquid-based cytology in the detection of urothelial neoplasm: A retrospective study. Cytojournal. 2017;14:27. [DOI:10.4103/cytojournal.cytojournal_23_17] [PMID] [PMCID]
  35. Lenos M, Katafigiotis I, Vrettou K, Papaioannou D, Malta F, Trigka EA, et al. Evaluation of double immunocytochemical staining for CK20 and P53 as a potential adjunct to cytology for urothelial cancer diagnosis. Cytopathology Off J Br Soc Clin Cytol. 2017;28(2):96-102. [DOI:10.1111/cyt.12386] [PMID]
  36. Choi SY, Kim KH, Suh KS, Yeo MK. Diagnostic significance of dual immunocytochemical staining of p53/cytokeratin20 on liquid-based urine cytology to detect urothelial carcinoma. Cytojournal. 2020;17:3. [PMID] [PMCID] [DOI:10.25259/Cytojournal_88_2019]
  37. Das S, Roy Chowdhury AR, Basu S, Lath A. A Study on Association of Urine Cytology as Reported by the Paris System with Histopathology and p53 Expression in Urinary Bladder Epithelial Neoplasms. J Clin Diagn Res. 2019;13(10). [DOI:10.7860/JCDR/2019/42014.13201]
  38. Abdullah LS. The value of urine cytology in the diagnosis of bladder cancer. Cytopathological correlation. Saudi Med J. 2013 Sep 1;34(9):937-41.
  39. Moatamed NA, Rao JY, Alexanian S, Cobarrubias M, Levin M, Lu D, et al. ProEx C as an adjunct marker to improve cytological detection of urothelial carcinoma in urinary specimens. Cancer Cytopathol. 2013;121(6):320-8. [DOI:10.1002/cncy.21264] [PMID]
  40. Raica M, Zylis D, Cîmpean AM. Cytokeratin 20, 34betaE12 and overexpression of HER-2/neu in urine cytology as predictors of recurrences in superficial urothelial carcinoma. Romanian Journal Morphol Embryol Rev Roum Morphol Embryol. 2005;46(1):11-5.
  41. Darabi M, Tayebi MN, Mahdavi R, Arab D. p53 protein in serum and urine samples of patients with bladder transitional cell carcinoma and its overexpression in tumoral tissue. Urol J. 2006;3(4):216-9.
  42. El-Gamal EM, Gouida MS. Quantitative changes in p53, Bcl-2 and apoptosis in blood and urine of bladder cancer patients. Clin Lab. 2013;59(3-4):349-58. [DOI:10.7754/Clin.Lab.2012.111224] [PMID]
  43. Piaton E, Faÿnel J, Ruffion A, Lopez JG, Perrin P, Devonec M. p53 immunodetection of liquid-based processed urinary samples helps to identify bladder tumours with a higher risk of progression. Br J Cancer. 2005;93(2):242-7. [DOI:10.1038/sj.bjc.6602684] [PMID] [PMCID]
  44. Sullivan PS, Chan JB, Levin MR, Rao J. Urine cytology and adjunct markers for detection and surveillance of bladder cancer. Am J Translation Res. 2010;2(4):412-40.
  45. Wegelin O, Bartels DWM, Tromp E, Kuypers KC, Van Melick HH. The effects of instrumentation on Urine Cytology and CK-20 Analysis for the Detection of Bladder Cancer. Urology. 2015;86(4):772-6. [DOI:10.1016/j.urology.2015.06.035] [PMID]
  46. Sakamoto H, Takenaka M, Ushimaru K, Tanaka T. Use of liquid-based cytology (LBC) and cell blocks from cell remnants for cytologic, immunohistochemical, and immunocytochemical diagnosis of malignancy. Open J Pathol [Internet]. 2012 Jul 18 [cited 2022 Apr 29];2(3). Available from: http://www.scirp.org/journal/PaperInformation.aspx?PaperID=21116
  47. Sioutopoulou DO, Kampas LI, Gerasimidou D, Valeri RM, Boukovinas I, Tsavdaridis D, et al. Diagnosis of metastatic tumors in cerebrospinal fluid samples using thin-layer cytology. Acta Cytol. 2008;52(3):304-8. [DOI:10.1159/000325511] [PMID].
Iranian Journal of Pathology
Volume 18, Issue 3
July 2023
Pages 257-269
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History
  • Receive Date: 07 November 2022
  • Revise Date: 15 January 2023
  • Accept Date: 15 March 2023
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