Immunohistochemical Expression of Fibroblast Growth Factor Receptor 3 and Cyclooxygenase-2 in Urinary Bladder Carcinomas with Correlation of Schistosomiasis in Egyptian Patients
DOI:
https://doi.org/10.3889/oamjms.2020.4627Keywords:
Urothelial carcinoma, Bladder Cancer, FGFR3, COX-2, SchistosomiasisAbstract
BACKGROUND: In Egypt, schistosomal infestation is a leading cause of bladder cancer. A mutation in the fibroblast growth factor receptor 3 (FGFR-3) gene is the most common and most specific genetic abnormality in bladder cancer. Similarly, cyclooxygenase-2 (COX-2) is an inducible, pro-inflammatory enzyme with previous studies showing higher expression in schistosomal-associated bladder cancer.
AIM OF THE STUDY: The aim of the study was to evaluate the immunohistochemical expression of FGFR3 and COX2 in bladder carcinoma and correlates their expression to the associated schistosomal infestation to implicate possible therapeutic treatments.
MATERIALS AND METHODS: This retrospective study included a total of 90 cases of archived, formalin fixed, paraffin-embedded tissue blocks that included variable subtypes and grades of urothelial carcinomas. Immunohistochemistry for expression of FGFR-3 and COX2 was performed using a standard avidin-biotin-peroxidase system.
RESULTS: About 73.3% of the total cases (66 cases) showed variable positive reactivity for FGFR3, of which 33.3% (22 cases) were associated with bilharzia infection. A statistically significant correlation was detected between FGFR-3 and tumor size, grade, histologic subtype, LN status, lymphovascular invasion, and stage. About 83.3% of the total cases (75 cases) showed variable positive immunoreactivity for COX-2, of which 37.3% (28 cases) were bilharzial-associated. A positive correlation was established between COX-2 and grade, concomitant in situ changes and cases associated with bilharzia infection.
CONCLUSION: FGFR-3 can be used as a prognostic marker for low-grade urothelial tumors. Results also portray that COX-2 has an inflammatory inciting role in bladder carcinoma development, especially in patients with a history of schistosomiasis (bilharziasis). Both COX-2 and FGFR-3 should be explored further for its use alone or in combination with conventional treatment, to reduce the recurrence rate and progression of superficial (low grade) tumors.
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Batista R, Vinagre N, Meireles S, Vinagre J, Prazeres H, Leão R, et al. Biomarkers for bladder cancer diagnosis and surveillance: A comprehensive review. Diagnostics (Basel). 2020;10(1):E39. https://doi.org/10.3390/diagnostics10010039 PMid:31941070
Martino ED, Tomlinson DC, Knowles MA. A decade of FGF receptor research in bladder cancer: Past, present, and future challenges. Adv Urol. 2012;2012:429213. https://doi. org/10.1155/2012/429213 PMid:22899908
Pandith AA, Shah ZA, Siddiqi MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urol Oncol. 2013;31(4):398-406. https://doi. org/10.1016/j.urolonc.2010.07.014 PMid:20822928
Goodison S, Rosser CJ, Urquidi V. Bladder cancer detection and monitoring: Assessment of urine-and blood-based marker tests. Mol Diagn Ther. 2013;17(2):71-84. https://doi.org/10.1007/ s40291-013-0023-x PMid:23479428
Moussa M, Omran Z, Nosseir M, Lotfy A, Swellam T. Cyclooxygenase-2 expression on urothelial and inflammatory cells of cystoscopic biopsies and urine cytology as a possible predictive marker for bladder carcinoma. APMIS. 2009;117(1):45- 52. https://doi.org/10.1111/j.1600-0463.2008.00014.x PMid:19161536
Guancial EA, Werner L, Bellmunt J, Bamias A, Choueiri TK, Ross R, et al. FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder. Cancer Med. 2014;3(4):835-44. https://doi.org/10.1002/cam4.262 PMid:24846059
Aliramaji A, Kaseean A, Pasha YR, Shafi H, Kamali S, Safari M, et al. Age distribution types of bladder cancers and their relationship with opium consumption and smoking. Caspian J Intern Med. 2015;6(2):82-6. PMid:26221505
Felix AS, Soliman AS, Khaled H, Zaghloul MS, Banerjee M, El-Baradie M, et al. The changing patterns of bladder cancer in Egypt over the past 26 years. Cancer Causes Control. 2008;19(4):421-9. https://doi.org/10.1007/s10552-007-9104-7 PMid:18188671
Gust KM, Mcconkey DJ, Awrey S, Hegarty PK, Qing J, Bondaruk J, et al. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol Cancer Ther. 2013;12(7):1245-54. https://doi.org/10.1158/1535-7163. mct-12-1150 PMid:23657946
Kyritsi F, Loffredo CA, Zheng YL, Philips G, Amr S. Urinary bladder cancer in Egypt: Are there gender differences in its histopathological presentation? Adv Urol. 2018;2018:1-7. https://doi.org/10.1155/2018/3453808
Hammam O, Aboushousha T, El-Hindawi A, Khairy H, Khalil H, Kamel A, et al. Expression of FGFR3 protein and gene amplification in urinary bladder lesions in relation to schistosomiasis. Open Access Maced J Med Sci. 2017;(2):160-6. https://doi.org/10.3889/oamjms.2017.048 PMid:28507621
Junker K, Oers JM, Zwarthoff EC, Kania I, Schubert J, Hartmann A. Fibroblast growth factor receptor 3 mutations in bladder tumors correlate with low frequency of chromosome alterations. Neoplasia. 2008;10(1):1-7. https://doi.org/10.1593/ neo.07178 PMid:18231634
Maeng YH, Eun SY, Huh JS. Expression of fibroblast growth factor receptor 3 in the recurrence of non-muscle-invasive urothelial carcinoma of the bladder. Korean J Urol. 2010;51(2):94-100. https://doi.org/10.4111/kju.2010.51.2.94 PMid:20414420
Tomlinson D, Baldo O, Harnden P, Knowles M. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213(1):91-8. https:// doi.org/10.1002/path.2207 PMid:17668422
Poyet C, Hermanns T, Zhong Q, Drescher E, Eberli D, Burger M, et al. Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer. Oncol Lett. 2015;10(5):2753-60. https://doi.org/10.3892/ ol.2015.3691 PMid:26722237
Wakai K, Utsumi T, Yoneda K, Oka R, Endo T, Yano M, et al. Development and external validation of a nomogram to predict high-grade papillary bladder cancer before first-time transurethral resection of the bladder tumor. Int J Clin Oncol. 2018;23(5):957-64. https://doi.org/10.1007/s10147-018-1299-y PMid:29804156
Shapur N, Pode D, Katz R, Shapiro A, Yutkin V, Pizov G, al. Predicting the risk of high-grade bladder cancer using noninvasive data. Urol Int. 2011;87(3):319-24. https://doi. org/10.1159/000328635 PMid:21849760
Youssef RF, Lotan Y. Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer. ScientificWorldJournal. 2010;11:369-81. https://doi.org/10.1100/ tsw.2011.28 PMid:21336453
Thanan R, Murata M, Ma N, Hammam O, Wishahi M, El Leithy T, et al. Nuclear localization of COX-2 in relation to the expression of stemness markers in urinary bladder cancer. Mediators inflamm. 2012;2012:165879. https://doi.org/10.1155/2012/165879 PMid:22577245
Jacobs BL, Lee CT, Montie JE. Bladder cancer in 2010: How far have we come? CA Cancer J Clin. 2010;60(4):244-72. https:// doi.org/10.3322/caac.20077 PMid:20566675
Baldia PH, Maurer A, Heide T, Rose M, Stoehr R, Hartmann A, et al. Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: A putative therapeutic target for a small subgroup. Oncotarget. 2016;7(44):71429-39. https://doi.org/10.18632/oncotarget.12198 PMid:27669755
Martino ED, Tomlinson DC, Knowles MA. A decade of FGF receptor research in bladder cancer: Past, present, and future challenges. Adv Urol. 2012;2012:429213. https://doi. org/10.1155/2012/429213 PMid:22899908
Yamada Y, Nakamura K, Inoue Y, Naruse K, Aoki S, Taki T, et al. Cyclooxygenase-2 expression in invasive transitional cell carcinoma of the urinary bladder. Mol Med Rep. 2008;1(6):791-5. PMid:21479487
Ehdaie B, Sylvester R, Herr HW. Maintenance bacillus calmette-guérin treatment of non-muscle-invasive bladder cancer: A critical evaluation of the evidence. Eur Urol. 2013;64(4):579- 85. https://doi.org/10.1016/j.eururo.2013.05.027 PMid:23711538
Kluth LA, Black PC, Bochner BH, Catto J, Lerner SP, Stenzl A, et al. Prognostic and prediction tools in bladder cancer: A comprehensive review of the literature. Eur Urol. 2015;68(2):238-53. https://doi.org/10.1016/j.eururo.2015.01.032 PMid:25709027
El-Sheikh SS, Madaan S, Alhasso A, Abel P, Stamp G, Lalani EN. Cyclooxygenase-2: A possible target in schistosoma-associated bladder cancer. BJU Int. 2001;88(9):921-7. https:// doi.org/10.1046/j.1464-4096.2001.01649.x PMid:11851614
Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S. COX2/mPGES1/PGE2pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci. 2017;114(5):1117-22. https://doi.org/10.1073/pnas.1612920114
Casadei C, Dizman N, Schepisi G, Cursano MC, Basso U, Santini D, et al. Targeted therapies for advanced bladder cancer: New strategies with FGFR inhibitors. Ther Adv Med Oncol. 2019;11:5-9. https://doi.org/10.1177/1758835919890285 PMid:31803255
Ishida K, Hsieh MH. Understanding urogenital schistosomiasis-related bladder cancer: An update. Front Med. 2018;5:223. https://doi.org/10.3389/fmed.2018.00223 PMid:30159314
Hassan HE, Mohamed AA, Bakhiet AO, Ahmed HG. Immunohistochemical expression of COX2 and iNOS in bladder cancer and its association with urinary schistosomiasis among Sudanese patients. Infect Agents Cancer. 2013;8(1):9. https:// doi.org/10.1186/1750-9378-8-9 PMid:23414519
Mhawech-Fauceglia P, Cheney R, Fischer G, Beck A, Herrmann F. FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Eur J Surg Oncol. 2006;32(2):231-7. https://doi.org/10.1016/j.ejso.2005.11.018 PMid:16412606
Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: Results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. https://doi.org/10.1155/2014/437971 PMid:25328522
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