Reduced immunohistochemical PTEN staining is associated with higher progression rate and recurrence episodes in non-invasive low-grade papillary urothelial carcinoma of the bladder
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Non-invasive low-grade papillary urothelial carcinoma (NILGPUC) of the bladder is regarded as a relatively indolent disease. However, its propensity for frequent recurrences constitutes a major clinical problem. Additionally, there is a progression risk of 10–15% to either a higher grade and/or a higher stage disease in these tumors. The molecular factors that will predict recurrence and progression in low-grade pTa bladder carcinoma have not yet been elucidated. Herein, we investigated the association of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) alterations with recurrence and progression in NILGPUC using immunohistochemistry. Eighty-one cases of bladder cancer initially diagnosed as NILGPUC in a single institution with follow-up were encountered after searching medical records. Tissue microarrays (TMA) that contained both tumor and non-neoplastic mucosa from each case were constructed using paraffin blocks of transurethral resections. Sections from TMA blocks were stained immunohistochemically for PTEN protein and were evaluable in 76 cases. Any absence of staining was recorded and correlated with clinical findings. Ten patients (13.2%) showed progression and 41 (53.9%) showed recurrence. Reduced PTEN expression was observed in 29 cases (38.1%). Cases with reduced PTEN had higher progression rate compared to cases with intact PTEN (p = 0.026). Tumor relapse was more frequent in cases with reduced PTEN (65.5 vs 46.8%), but this difference was not statistically significant (p = 0.112). On the other hand, decreased PTEN expression was associated with higher number of recurrence episodes (p = 0.002). PTEN seems to have a link with the disease course in NILGPUC of the bladder.
KeywordsBladder Urothelial carcinoma Bladder cancer Non-invasive PTEN
This research was supported by a grant from the Scientific Research Unit of Hacettepe University (grant no. 012 D06 101 014).
Compliance with ethical standards
The study was approved by the institutional ethics review board.
Conflict of interests
The authors declare that they have no conflict of interest.
- 3.Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71(3):447–461. https://doi.org/10.1016/j.eururo.2016.05.041 CrossRefPubMedGoogle Scholar
- 4.Miyamoto H, Brimo F, Schultz L, Ye H, Miller JS, Fajardo DA, Lee TK, Epstein JI, Netto GJ (2010) 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 134(8):1160–1163. https://doi.org/10.1043/2009-0403-OA.1 PubMedGoogle Scholar
- 5.Kobayashi H, Kikuchi E, Mikami S, Maeda T, Tanaka N, Miyajima A, Nakagawa K, Oya M (2014) Long term follow-up in patients with initially diagnosed low grade ta non-muscle invasive bladder tumors: tumor recurrence and worsening progression. BMC Urol 14(1):5. https://doi.org/10.1186/1471-2490-14-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13 (5):283–296. doi: https://doi.org/10.1038/nrm3330
- 7.Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447):67–73. https://doi.org/10.1038/nature12113 CrossRefPubMedGoogle Scholar
- 8.Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA (2011) The genomic complexity of primary human prostate cancer. Nature 470(7333):214–220. https://doi.org/10.1038/nature09744 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Wang DS, Rieger-Christ K, Latini JM, Moinzadeh A, Stoffel J, Pezza JA, Saini K, Libertino JA, Summerhayes IC (2000) Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer 88(4):620–625. https://doi.org/10.1002/1097-0215(20001115)88:4<620::AID-IJC16>3.0.CO;2-Z CrossRefPubMedGoogle Scholar
- 14.Schultz L, Albadine R, Hicks J, Jadallah S, DeMarzo AM, Chen YB, Nielsen ME, Gonzalgo ML, Sidransky D, Schoenberg M, Netto GJ (2010) Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy. Cancer 116(23):5517–5526. https://doi.org/10.1002/cncr.25502 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Picanco-Albuquerque CG, Morais CL, Carvalho FL, Peskoe SB, Hicks JL, Ludkovski O, Vidotto T, Fedor H, Humphreys E, Han M, Platz EA, De Marzo AM, Berman DM, Lotan TL, Squire JA (2016) In prostate cancer needle biopsies, detections of PTEN loss by fluorescence in situ hybridization (FISH) and by immunohistochemistry (IHC) are concordant and show consistent association with upgrading. Virchows Arch 468(5):607–617. https://doi.org/10.1007/s00428-016-1904-2 CrossRefPubMedGoogle Scholar
- 16.Djordjevic B, Hennessy BT, Li J, Barkoh BA, Luthra R, Mills GB, Broaddus RR (2012) Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol 25(5):699–708. https://doi.org/10.1038/modpathol.2011.208 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM (2011) PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 17(20):6563–6573. https://doi.org/10.1158/1078-0432.CCR-11-1244 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Holmang S, Andius P, Hedelin H, Wester K, Busch C, Johansson SL (2001) Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 165(4):1124–1130. https://doi.org/10.1016/S0022-5347(05)66443-9 CrossRefPubMedGoogle Scholar
- 19.Liu S, Hou J, Zhang H, Wu Y, Hu M, Zhang L, Xu J, Na R, Jiang H, Ding Q (2015) The evaluation of the risk factors for non-muscle invasive bladder cancer (NMIBC) recurrence after transurethral resection (TURBt) in Chinese population. PLoS One 10(4):e0123617. https://doi.org/10.1371/journal.pone.0123617 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Pich A, Chiusa L, Formiconi A, Galliano D, Bortolin P, Comino A, Navone R (2002) Proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder. Cancer 95(4):784–790CrossRefPubMedGoogle Scholar
- 21.Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C, Johansson SL (1999) Recurrence and progression in low grade papillary urothelial tumors. J Urol 162 (3, part 1):702-707. doi: https://doi.org/10.1097/00005392-199909010-00019
- 22.Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49(3):466–477. https://doi.org/10.1016/j.eururo.2005.12.031 CrossRefPubMedGoogle Scholar
- 24.Miyake M, Sugano K, Sugino H, Imai K, Matsumoto E, Maeda K, Fukuzono S, Ichikawa H, Kawashima K, Hirabayashi K (2010) Fibroblast growth factor receptor 3 mutation in voided urine is a useful diagnostic marker and significant indicator of tumor recurrence in non-muscle invasive bladder cancer. Cancer Sci 101(1):250–258. https://doi.org/10.1111/j.1349-7006.2009.01334.x CrossRefPubMedGoogle Scholar
- 25.Zuiverloon TC, van der Aa MN, van der Kwast T, Steyerberg EW, Lingsma HF, Bangma C, Zwarthoff EC (2010) FGFR3 mutation analysis on voided urine for surveillance of patients with low-grade nonmuscle invasive bladder cancer. Clin Cancer Res 16(11):3011–3018. https://doi.org/10.1158/1078-0432.CCR-09-3013 CrossRefPubMedGoogle Scholar
- 27.van Rhijn BW, Zuiverloon TC, Vis AN, Radvanyi F, van Leenders GJ, Ooms BC, Kirkels WJ, Lockwood GA, Boeve ER, Jobsis AC, Zwarthoff EC, van der Kwast TH (2010) Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol 58(3):433–441. https://doi.org/10.1016/j.eururo.2010.05.043 CrossRefPubMedGoogle Scholar
- 29.Lotan TL, Carvalho FL, Peskoe SB, Hicks JL, Good J, Fedor HL, Humphreys E, Han M, Platz EA, Squire JA (2015) PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol 28(1):128–137. https://doi.org/10.1038/modpathol.2014.85 CrossRefPubMedGoogle Scholar
- 30.Schmitz M, Grignard G, Margue C, Dippel W, Capesius C, Mossong J, Nathan M, Giacchi S, Scheiden R, Kieffer N (2007) Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer 120(6):1284–1292. https://doi.org/10.1002/ijc.22359 CrossRefPubMedGoogle Scholar