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01-06-2018 | Original Article

Reduced immunohistochemical PTEN staining is associated with higher progression rate and recurrence episodes in non-invasive low-grade papillary urothelial carcinoma of the bladder

Authors: Ibrahim Kulac, Sehbal Arslankoz, George J. Netto, Dilek Ertoy Baydar

Published in: Virchows Archiv | Issue 6/2018

Abstract

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.

Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387 CrossRefPubMed

Vollmer RT (2016) A review of outcomes for stage Ta bladder tumors. Am J Clin Pathol 146(2):215–220. https://doi.org/10.1093/ajcp/aqw103 CrossRefPubMed

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 CrossRefPubMed

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 PubMedCrossRef

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 CrossRefPubMedPubMedCentral

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

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA (2009) Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res 15(19):6008–6017. https://doi.org/10.1158/1078-0432.CCR-09-0898 CrossRefPubMed

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 CrossRefPubMed

11.

Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH, Matos T, Shen MM, Cordon-Cardo C, Abate-Shen C (2009) Inactivation of p53 and PTEN promotes invasive bladder cancer. Genes Dev 23(6):675–680. https://doi.org/10.1101/gad.1772909 CrossRefPubMedPubMedCentral

12.

Aveyard JS, Skilleter A, Habuchi T, Knowles MA (1999) Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80(5–6):904–908. https://doi.org/10.1038/sj.bjc.6690439 CrossRefPubMedPubMedCentral

13.

Sun CH, Chang YH, Pan CC (2011) Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology 58(7):1054–1063. https://doi.org/10.1111/j.1365-2559.2011.03856.x CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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):784–790CrossRefPubMed

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 CrossRefPubMed

23.

Netto GJ (2011) Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol 9(1):41–51. https://doi.org/10.1038/nrurol.2011.193 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

26.

Cheng L, Zhang S, Davidson DD, MacLennan GT, Koch MO, Montironi R, Lopez-Beltran A (2009) Molecular determinants of tumor recurrence in the urinary bladder. Future Oncol 5(6):843–857. https://doi.org/10.2217/fon.09.50 CrossRefPubMed

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 CrossRefPubMed

28.

Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11(4):289–301. https://doi.org/10.1038/nrc3037 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

31.

McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR (1999) Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59(17):4291–4296PubMed

Title: Reduced immunohistochemical PTEN staining is associated with higher progression rate and recurrence episodes in non-invasive low-grade papillary urothelial carcinoma of the bladder
Authors: Ibrahim Kulac
Sehbal Arslankoz
George J. Netto
Dilek Ertoy Baydar
Publication date: 01-06-2018
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 6/2018
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-018-2302-8

At a glance: The STEP trials

Springer Medicine

Reduced immunohistochemical PTEN staining is associated with higher progression rate and recurrence episodes in non-invasive low-grade papillary urothelial carcinoma of the bladder

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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