Skip to main content
Erschienen in: Pathology & Oncology Research 4/2016

24.05.2016 | Original Article

P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas

verfasst von: Banu Sarsik, Basak Doganavsargil, Adnan Simsir, Ayse Yazici, Burcin Pehlivanoglu, Cag Cal, Sait Sen

Erschienen in: Pathology & Oncology Research | Ausgabe 4/2016

Einloggen, um Zugang zu erhalten

Abstract

p21 and p27 are members of cyclin-dependent kinase family, which function as tumor suppressors and they are involved in development and progression of several malignancies. We investigated their expression in upper urinary tract urothelial carcinoma (UUTUC). Radical nephroureterectomy materials of 34 patients were assessed by immunohistochemistry to evaluate expression of p21 and p27 in UUTUC. Results were correlated with various clinicopathological variables as age, gender, tumor grade and stage, tumor architecture, multifocality, subsequent bladder carcinoma development and clinical outcome.
p21 and p27 expression was observed in 52.9 % (n = 18) and 88.2 % (n = 30), respectively. A total of 21 tumors (61.7 %) showed either total loss of p21 expression (n = 16, 47 %) or lower expression (n = 5, 14.7 %). No correlation was found between p21 expression and clinicopathologic variables. Cases showing total loss or lower p27 expression (11.7 % and <25.6 %, respectively) (n = 19, 55.8 %) constituted 67.6 % (n = 23) of the cases totally. This loss or lower p27 expression correlated with a shorter overall survival in both univariate and multivariate analysis (p = 0.039 and p = 0.037, respectively). None of the noninvasive tumors (papillary and nodular tumors) showed loss of p27 (p = 0.016) while 33.3 % of invasive ones showed p27 loss. Noninvasive tumor architecture also correlated with subsequent bladder carcinoma development (p = 0.032) while invasive tumor architecture correlated with advanced stage (T3 and T4) (p = 0.003). p27 is widely expressed in UUTUC, while p21 expression is observed in half of the cases. Loss of p27 expression correlated with tumor architecture and overall survival in UUTUC. However, further research is needed to assess their role in UUTUC.
Literatur
1.
Zurück zum Zitat Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249CrossRefPubMed
2.
Zurück zum Zitat Novara G, De Marco V, Gottardo F, Dalpiaz O, Bouygues V, Galfano A, et al. (2007) Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multiinstitutional dataset from 3 European centers. Cancer 110(8):1715–1722CrossRefPubMed Novara G, De Marco V, Gottardo F, Dalpiaz O, Bouygues V, Galfano A, et al. (2007) Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multiinstitutional dataset from 3 European centers. Cancer 110(8):1715–1722CrossRefPubMed
3.
Zurück zum Zitat Chromecki TF, Cha EK, Fajkovic H, Margulis V, Novara G, Scherr DS, et al. (2012) The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. Eur Urol 61(2):245–253CrossRefPubMed Chromecki TF, Cha EK, Fajkovic H, Margulis V, Novara G, Scherr DS, et al. (2012) The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. Eur Urol 61(2):245–253CrossRefPubMed
4.
Zurück zum Zitat Verhoest G, Shariat SF, Chromecki TM, Raman JD, Margulis V, Novara G, et al. (2011) Predictive factors of recurrence and survival of upper tract urothelial carcinomas. World J Urol 29(4):495–501CrossRefPubMedPubMedCentral Verhoest G, Shariat SF, Chromecki TM, Raman JD, Margulis V, Novara G, et al. (2011) Predictive factors of recurrence and survival of upper tract urothelial carcinomas. World J Urol 29(4):495–501CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. (1997) Decreased levels of the cell-cycle inhibitor p27Kip1 protein; prognostic implications in primary breast cancer. Nat Med 3(2):227–230CrossRefPubMed Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. (1997) Decreased levels of the cell-cycle inhibitor p27Kip1 protein; prognostic implications in primary breast cancer. Nat Med 3(2):227–230CrossRefPubMed
6.
Zurück zum Zitat Cote RJ, Susan Y, Groshen S, Alexander GM, Gatti LA, Firpo EJ, et al. (1998) Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst 90(12):916–920CrossRefPubMed Cote RJ, Susan Y, Groshen S, Alexander GM, Gatti LA, Firpo EJ, et al. (1998) Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst 90(12):916–920CrossRefPubMed
7.
Zurück zum Zitat Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. (1997) Increased proteasomedependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3(2):231–234CrossRefPubMed Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. (1997) Increased proteasomedependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3(2):231–234CrossRefPubMed
8.
Zurück zum Zitat Shariat SF, Zlotta AR, Ashfaq R, Sagalowsky AI, Lotan Y (2007) Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 20(4):445–459CrossRefPubMed Shariat SF, Zlotta AR, Ashfaq R, Sagalowsky AI, Lotan Y (2007) Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 20(4):445–459CrossRefPubMed
9.
Zurück zum Zitat Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, et al. (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2):313–323CrossRefPubMedPubMedCentral Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, et al. (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2):313–323CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Korkolopoulou P, Konstantinidou AE, Thomas-Tsagli E, Christodoulou P, Kapralos P, Davaris P (2000) WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer. Appl Immunohistochem Mol Morphol 8(4):285–292PubMed Korkolopoulou P, Konstantinidou AE, Thomas-Tsagli E, Christodoulou P, Kapralos P, Davaris P (2000) WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer. Appl Immunohistochem Mol Morphol 8(4):285–292PubMed
11.
Zurück zum Zitat Shariat SF, Karakiewicz PI, Ashfaq R, Lerner SP, Palapattu GS, Cote RJ, et al. (2008) Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 112(2):315–325CrossRefPubMed Shariat SF, Karakiewicz PI, Ashfaq R, Lerner SP, Palapattu GS, Cote RJ, et al. (2008) Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 112(2):315–325CrossRefPubMed
12.
Zurück zum Zitat Matsushima H, Sasaki T, Goto T, Hosaka Y, Homma Y, Kitamura T, et al. (1998) Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. Hum Pathol 29(8):778–783CrossRefPubMed Matsushima H, Sasaki T, Goto T, Hosaka Y, Homma Y, Kitamura T, et al. (1998) Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. Hum Pathol 29(8):778–783CrossRefPubMed
13.
Zurück zum Zitat Masuda M, Takano Y, Iki M, Makiyama K, Ikeda I, Noguchi S, et al. (2000) Cyclin-dependent kinase inhibitor p27kip1 expression in transitional cell carcinoma of renal pelvis and ureter. Cancer Lett 150(2):183–189CrossRefPubMed Masuda M, Takano Y, Iki M, Makiyama K, Ikeda I, Noguchi S, et al. (2000) Cyclin-dependent kinase inhibitor p27kip1 expression in transitional cell carcinoma of renal pelvis and ureter. Cancer Lett 150(2):183–189CrossRefPubMed
14.
Zurück zum Zitat Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI (2000) Prognostic significance of p27kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int 86(1):14–19CrossRefPubMed Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI (2000) Prognostic significance of p27kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int 86(1):14–19CrossRefPubMed
15.
Zurück zum Zitat Fromont G, Rouprêt M, Amira N, Sibony M, Vallancien G, Validire P, et al. (2005) Tissue microarray analysis of the prognostic value of E-cadherin, Ki67, p53, p27, survivin and MSH2 expression in upper urinary tract transitional cell carcinoma. Eur Urol 48(5):764–770CrossRefPubMed Fromont G, Rouprêt M, Amira N, Sibony M, Vallancien G, Validire P, et al. (2005) Tissue microarray analysis of the prognostic value of E-cadherin, Ki67, p53, p27, survivin and MSH2 expression in upper urinary tract transitional cell carcinoma. Eur Urol 48(5):764–770CrossRefPubMed
16.
Zurück zum Zitat Gakis G, Schwentner C, Todenhöfer T, Stenzl A (2012) Current status of molecular markers for prognostication and outcome in invasive bladder cancer. BJU Int 110(2):233–237CrossRefPubMed Gakis G, Schwentner C, Todenhöfer T, Stenzl A (2012) Current status of molecular markers for prognostication and outcome in invasive bladder cancer. BJU Int 110(2):233–237CrossRefPubMed
17.
Zurück zum Zitat Simsir A, Sarsik B, Cureklibatir I, Sen S, Gunaydin G, Cal C (2011) Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and smoking status. Int Urol Nephrol 43(4):1039–1045CrossRefPubMed Simsir A, Sarsik B, Cureklibatir I, Sen S, Gunaydin G, Cal C (2011) Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and smoking status. Int Urol Nephrol 43(4):1039–1045CrossRefPubMed
18.
Zurück zum Zitat Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors, ed. 7. UICC International Union Against Cancer. Hoboken, NJ: Wiley-Blackwell; 2010. p. 258–265. Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors, ed. 7. UICC International Union Against Cancer. Hoboken, NJ: Wiley-Blackwell; 2010. p. 258–265.
19.
Zurück zum Zitat Eble JN, Sauter G, Epstein JI, et al. World Health Organization classification of tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon, France: IARC Press; 2004, p.90. Eble JN, Sauter G, Epstein JI, et al. World Health Organization classification of tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon, France: IARC Press; 2004, p.90.
20.
Zurück zum Zitat Remzi M, Haitel A, Margulis V, Karakiewicz P, Montorsi F, Kikuchi E, et al. (2009) Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 103(3):307–311CrossRefPubMed Remzi M, Haitel A, Margulis V, Karakiewicz P, Montorsi F, Kikuchi E, et al. (2009) Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 103(3):307–311CrossRefPubMed
21.
Zurück zum Zitat Doganavsargil B, Simsir A, Boyacioglu H, Cal C, Hekimgil M (2006) A comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neoplasia and prostate adenocarcinoma. BJU Int 97:644–648CrossRefPubMed Doganavsargil B, Simsir A, Boyacioglu H, Cal C, Hekimgil M (2006) A comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neoplasia and prostate adenocarcinoma. BJU Int 97:644–648CrossRefPubMed
22.
Zurück zum Zitat Romics I, Bánfi G, Székely E, Krenács T, Szende B (2008) Expression of p21(waf1/cip1), p27 (kip1), p63 and androgen receptor in low and high Gleason score prostate cancer. Pathol Oncol Res 14(3):307–311CrossRefPubMed Romics I, Bánfi G, Székely E, Krenács T, Szende B (2008) Expression of p21(waf1/cip1), p27 (kip1), p63 and androgen receptor in low and high Gleason score prostate cancer. Pathol Oncol Res 14(3):307–311CrossRefPubMed
23.
Zurück zum Zitat Huang LW, Seow KM, Lee CC, Lin YH, Pan HS, Chen HJ (2010) Decreased p21 expression in HPV-18 positive cervical carcinomas. Pathol Oncol Res 16(1):81–86CrossRefPubMed Huang LW, Seow KM, Lee CC, Lin YH, Pan HS, Chen HJ (2010) Decreased p21 expression in HPV-18 positive cervical carcinomas. Pathol Oncol Res 16(1):81–86CrossRefPubMed
24.
Zurück zum Zitat Fritsche HM, Novara G, Burger M, Gupta A, Matsumoto K, Kassouf W, et al. (2012) Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Urol Oncol 30(5):666–672CrossRefPubMed Fritsche HM, Novara G, Burger M, Gupta A, Matsumoto K, Kassouf W, et al. (2012) Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Urol Oncol 30(5):666–672CrossRefPubMed
25.
Zurück zum Zitat Margulis V, Youssef RF, Karakiewicz PI, Lotan Y, Wood CG, Zigeuner R, et al. (2010) Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J Urol 184(2):453–458CrossRefPubMed Margulis V, Youssef RF, Karakiewicz PI, Lotan Y, Wood CG, Zigeuner R, et al. (2010) Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J Urol 184(2):453–458CrossRefPubMed
26.
Zurück zum Zitat Franke KH, Miklosi M, Goebell P, Clasen S, Steinhoff C, Anastasiadis AG, et al. (2000) Cyclin-dependent kinase inhibitor P27 (KIP1) is expressed preferentially in early stages of urothelial carcinoma. Urology 56(4):689–695CrossRefPubMed Franke KH, Miklosi M, Goebell P, Clasen S, Steinhoff C, Anastasiadis AG, et al. (2000) Cyclin-dependent kinase inhibitor P27 (KIP1) is expressed preferentially in early stages of urothelial carcinoma. Urology 56(4):689–695CrossRefPubMed
27.
Zurück zum Zitat Hisataki T, Miyao N, Masumori N, Takahashi A, Sasai M, Yanase M, et al. (2000) Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 55(5):663–667CrossRefPubMed Hisataki T, Miyao N, Masumori N, Takahashi A, Sasai M, Yanase M, et al. (2000) Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 55(5):663–667CrossRefPubMed
28.
Zurück zum Zitat Koga F, Nagamatsu H, Ishimaru H, Mizuo T, Yoshida K (2001) Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 67(2):135–141CrossRefPubMed Koga F, Nagamatsu H, Ishimaru H, Mizuo T, Yoshida K (2001) Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 67(2):135–141CrossRefPubMed
29.
Zurück zum Zitat Raman JD, Ng CK, Scherr DS, Margulis V, Lotan Y, Bensalah K, et al. (2010) Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. Eur Urol 57(6):1072–1079CrossRefPubMed Raman JD, Ng CK, Scherr DS, Margulis V, Lotan Y, Bensalah K, et al. (2010) Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. Eur Urol 57(6):1072–1079CrossRefPubMed
30.
Zurück zum Zitat Clasen S, Schulz WA, Gerharz CD, Grimm MO, Christoph F, Schmitz-Dräger BJ (1998) Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. Br J Cancer 77(4):515–521CrossRefPubMedPubMedCentral Clasen S, Schulz WA, Gerharz CD, Grimm MO, Christoph F, Schmitz-Dräger BJ (1998) Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. Br J Cancer 77(4):515–521CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Zlotta AR, Noel JC, Fayt I, Drowart A, Van Vooren JP, Huygen K, et al. (1999) Correlation and prognostic significance of p53, p21 WAF1/CIP1 and Ki67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy. J Urol 161(3):792–798CrossRefPubMed Zlotta AR, Noel JC, Fayt I, Drowart A, Van Vooren JP, Huygen K, et al. (1999) Correlation and prognostic significance of p53, p21 WAF1/CIP1 and Ki67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy. J Urol 161(3):792–798CrossRefPubMed
32.
Zurück zum Zitat Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG, et al. (1998) Effect of p21 WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90(14):1072–1079CrossRefPubMed Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG, et al. (1998) Effect of p21 WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90(14):1072–1079CrossRefPubMed
33.
Zurück zum Zitat Philipp-Staheli J, Kim KH, Liggitt D, Gurley KE, Longton G, Kemp CJ (2004) Distinct roles for p53, 27Kip1, and p21Cip1 during tumor development. Oncogene 23(4):905–913CrossRefPubMed Philipp-Staheli J, Kim KH, Liggitt D, Gurley KE, Longton G, Kemp CJ (2004) Distinct roles for p53, 27Kip1, and p21Cip1 during tumor development. Oncogene 23(4):905–913CrossRefPubMed
Metadaten
Titel
P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas
verfasst von
Banu Sarsik
Basak Doganavsargil
Adnan Simsir
Ayse Yazici
Burcin Pehlivanoglu
Cag Cal
Sait Sen
Publikationsdatum
24.05.2016
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 4/2016
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0075-4

Weitere Artikel der Ausgabe 4/2016

Pathology & Oncology Research 4/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.