Introduction: Urine cytology is a common method for detection of urothelial carcinoma (UC), however, is not high sensitivity. Improvement of the accuracy of cytodiagnosis using immunocytostaining as an auxiliary method is needed. This study aimed to determine the cytodiagnostic usefulness of peroxisome proliferator-activated receptor-gamma (PPAR-γ) immunocytostaining in urine cytology for the detection of UCs, particularly low-grade urothelial carcinomas (LGUC). Methods: PPAR-γ immunocytostaining was performed for 37 UC cases and 26 benign cases. Among the UC cases, 22 cases were of the papillary proliferation type, not including the mixed type comprising both papillary and flat growth. Fifteen LGUC cases of all papillary proliferation types were included. For comparison, the same samples were also immunocytostained for p53 and Ki-67. Results: Of the UC cases, 25 of 37 were positive for PPAR-γ, while 24 of the 26 benign cases were PPAR-γ-negative. Regardless of histological grading, 13 of the 22 UC cases with papillary proliferation were PPAR-γ-positive. In particular, PPAR-γ immunocytostaining showed higher sensitivity for LGUC cases than that of the other biomarkers. Regarding LGUC specifically, 4 of 10 cases not identified by primary cytology were detected by PPAR-γ immunocytostaining. Conclusion: PPAR-γ immunocytostaining enhances the accuracy of urine cytodiagnosis. Furthermore, PPAR-γ is a more useful immunobiomarker in urine cytology than p53 and Ki-67, the commonly used immunobiomarkers for malignant cell detection.

1.
Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137(1):354–66.
2.
Tsubouchi Y, Sano H, Kawahito Y, Mukai S, Yamada R, Kohno M, et al. Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis. Biochem Biophys Res Commun. 2000;270(2):400–5.
3.
Michael MS, Badr MZ, Badawi AF. Inhibition of cyclooxygenase-2 and activation of peroxisome proliferator-activated receptor-gamma synergistically induces apoptosis and inhibits growth of human breast cancer cells. Int J Mol Med. 2003;11(6):733–6.
4.
Lv S, Wang W, Wang H, Zhu Y, Lei C. PPARγ activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway. BMC Cancer. 2019;19(1):204.
5.
Tanaka S, Tokuhara Y, Hosokawa S, Ohsaki H, Morinishi T, Yamamoto T, et al. Overexpression of the PPAR-γ protein in primary Ta/T1 non-muscle-invasive urothelial carcinoma. Mol Clin Oncol. 2022;16(2):36.
6.
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. Cytopathology. 2016;27(6):456–64.
7.
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.
8.
Ogata DC, Marcondes CA, Tuon FF, Busato WF, Cavalli G, Czeczko LE. Superficial papillary urothelial neoplasms of the bladder (PTA E PT1): correlation of expression of P53, KI-67 and CK20 with histologic grade, recurrence and tumor progression. Rev Col Bras Cir. 2012;39(5):394–400.
9.
Singh M, Mockler D, Akalin A, Burke S, Shroyer AL, Shroyer KR. Immunocytochemical colocalization of P16(INK4a) and Ki-67 predicts CIN2/3 and AIS/adenocarcinoma. Cancer Cytopathol. 2012;120(1):26–34.
10.
Pan Y, Yuan Y, Liu G, Wei Y. P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients. PLoS One. 2017;12(2):e0172324.
11.
Kim YS, Kim HG, Han J, Hur CJ, Kim BS, Jung JT, et al. The significance of p53 and K-ras immunocytochemical staining in the diagnosis of malignant biliary obstruction by brush cytology during ERCP. Gut Liver. 2010;4(2):219–25.
12.
Nguyen JK, Przybycin CG, McKenney JK, Magi-Galluzzi C. Immunohistochemical staining patterns of Ki-67 and p53 in florid reactive urothelial atypia and urothelial carcinoma in situ demonstrate significant overlap. Hum Pathol. 2020;98:81–8.
13.
Yun SH, Roh MS, Jeong JS, Park JI. Peroxisome proliferator-activated receptor γ coactivator-1α is a predictor of lymph node metastasis and poor prognosis in human colorectal cancer. Ann Diagn Pathol. 2018;33:11–6.
14.
Zhang GY, Ahmed N, Riley C, Oliva K, Barker G, Quinn MA, et al. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer. 2005;92(1):113–9.
15.
Mylona E, Giannopoulou I, Diamantopoulou K, Bakarakos P, Nomikos A, Zervas A, et al. Peroxisome proliferator-activated receptor gamma expression in urothelial carcinomas of the bladder: association with differentiation, proliferation and clinical outcome. Eur J Surg Oncol. 2009;35(2):197–201.
16.
Bansal S, Pathuthara S, Joseph S, Dighe S, Menon S, Desai SB. Is diagnosis of low-grade urothelial carcinoma possible in urine cytology?J Cytol. 2021;38(2):64–8.
17.
VandenBussche CJ, Chandra A, Heymann JJ, McCroskey Z, Owens CL, Schubert PT, et al. Negative for high-grade urothelial carcinoma (NHGUC). In: Wojcik EM, Kurtycz DF, Rosenthal DL, editors. The Paris System for reporting urinary cytology. Cham: Springer International Publishing; 2022. p. 21–62.
18.
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. 2013;121(10):591–7.
19.
Kim JY, Kim HJ. A comparison between ThinPrep monolayer and cytospin cytology for the detection of bladder cancer. Korean J Urol. 2014;55(6):390–4.
20.
Yafi FA, Brimo F, Auger M, Aprikian A, Tanguay S, Kassouf W. Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urol Oncol. 2014;32(1):27.e1–6.
21.
Alameda F, Juanpere N, Pijuan L, Lloveras B, Gimeno J, Baró T, et al. Value of p16(INK4a) in the diagnosis of low-grade urothelial carcinoma of the urinary bladder in urinary cytology. Cancer Cytopathol. 2012;120(4):276–82.
22.
Østbye KM, Pedersen MK, Sauer T. Immunocytochemical expression of Ki-67/p16 in normal, atypical, and neoplastic cells in urine cytology using BD SurePath™ as preparation method. Cytojournal. 2019;16:26.
23.
Tanaka S, Naritomi M, Monobe Y, Ariyasu S. The inclusion of nuclear area improves the Paris system for reporting urinary cytology. Cytopathology. 2023;34(2):106–12.
24.
Miyamoto H, Brimo F, Schultz L, Ye H, Miller JS, Fajardo DA, et al. Low-grade papillary urothelial carcinoma of the urinary bladder: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center. Arch Pathol Lab Med. 2010;134(8):1160–3.
25.
Van Every MJ, Dancik G, Paramesh V, Gurda GT, Meier DR, Cash SE, et al. Genomic case report of a low grade bladder tumor metastasis to lung. BMC Urol. 2018;18(1):74.
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