Virchows Archiv

, Volume 462, Issue 1, pp 101–107 | Cite as

Nuclear, but not cytoplasmic, localization of survivin as a negative prognostic factor for survival in upper urinary tract urothelial carcinoma

  • Hiroshi KitamuraEmail author
  • Toshihiko Torigoe
  • Yoshihiko Hirohashi
  • Hiroko Asanuma
  • Ryuta Inoue
  • Sachiyo Nishida
  • Toshiaki Tanaka
  • Naoya Masumori
  • Noriyuki Sato
  • Taiji Tsukamoto
Original Article


Survivin, a member of the inhibitor of apoptosis protein gene family, inhibits apoptosis and promotes mitosis. We determined whether nuclear or cytoplasmic localization of survivin could predict survival of patients with upper urinary tract urothelial carcinoma (UUTUC). Immunohistochemical staining for survivin was carried out on archival specimens from 125 consecutive patients with UUTUC who underwent radical nephroureterectomy. Nuclear and cytoplasmic staining of survivin was scored and compared with clinicopathologic features and cancer-specific survival (CSS). Nuclear expression of survivin was significantly correlated with tumor grade (p < 0.001), lymphovascular invasion (p = 0.022) and poor survival with an estimated 5-year CSS probability of 54 % for tumors with nuclear expression of survivin vs. 73 % for those without nuclear expression of survivin (hazard ratio = 2.19; 95 % confidence interval = 1.02–4.70; p = 0.043). The 5-year cancer-specific survival rates of patients with cytoplasmic survivin-negative and -positive tumors were 66 and 67 %, respectively. There was no difference in survival between patients with cytoplasmic survivin-negative tumors and those with cytoplasmic survivin-positive tumors. Using univariate analysis, nuclear survivin expression, tumor grade, pathological T stage, pathological N stage, and lymphovascular invasion were the predictive variables for CSS. In contrast, cytoplasmic survivin expression had no prognostic relevance. These data suggest that nuclear accumulation of survivin represents biologic aggressiveness and that nuclear survivin is a negative prognostic marker in patients with resected UUTUC.


Survivin Urothelial carcinoma Upper urinary tract Survival 


Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Roupret M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R, Babjuk M, Oosterlinck W (2011) European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol 59(4):584–594. doi: 10.1016/j.eururo.2010.12.042 PubMedCrossRefGoogle Scholar
  2. 2.
    Kikuchi E, Margulis V, Karakiewicz PI, Roscigno M, Mikami S, Lotan Y, Remzi M, Bolenz C, Langner C, Weizer A, Montorsi F, Bensalah K, Koppie TM, Fernandez MI, Raman JD, Kassouf W, Wood CG, Suardi N, Oya M, Shariat SF (2009) Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma. J Clin Oncol 27(4):612–618. doi: 10.1200/JCO.2008.17.2361 PubMedCrossRefGoogle Scholar
  3. 3.
    Kim DS, Lee YH, Cho KS, Cho NH, Chung BH, Hong SJ (2010) Lymphovascular invasion and pT stage are prognostic factors in patients treated with radical nephroureterectomy for localized upper urinary tract transitional cell carcinoma. Urology 75(2):328–332. doi: 10.1016/j.urology.2009.07.1350 PubMedCrossRefGoogle Scholar
  4. 4.
    Novara G, Matsumoto K, Kassouf W, Walton TJ, Fritsche HM, Bastian PJ, Martinez-Salamanca JI, Seitz C, Lemberger RJ, Burger M, El-Hakim A, Baba S, Martignoni G, Gupta A, Karakiewicz PI, Ficarra V, Shariat SF (2010) Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract: an international validation study. Eur Urol 57(6):1064–1071. doi: 10.1016/j.eururo.2009.12.029 PubMedCrossRefGoogle Scholar
  5. 5.
    Zigeuner R, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Weizer A, Kikuchi E, Remzi M, Raman JD, Bolenz C, Bensalah K, Capitanio U, Koppie TM, Kassouf W, Sircar K, Patard JJ, Fernandez MI, Wood CG, Montorsi F, Strobel P, Wheat JC, Haitel A, Oya M, Guo CC, Ng C, Chade DC, Sagalowsky A, Langner C (2010) Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract. Eur Urol 57(4):575–581. doi: 10.1016/j.eururo.2009.11.035 PubMedCrossRefGoogle Scholar
  6. 6.
    Seitz C, Gupta A, Shariat SF, Matsumoto K, Kassouf W, Walton TJ, Fritsche HM, Otto W, Tritschler S, Bastian PJ, Carballido J, Ficarra V, Karakiewicz PI, Artibani W, Mazzoleni G, Novara G (2010) Association of tumor necrosis with pathological features and clinical outcome in 754 patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma: an international validation study. J Urol 184(5):1895–1900. doi: 10.1016/j.juro.2010.06.106 PubMedCrossRefGoogle Scholar
  7. 7.
    Remzi M, Haitel A, Margulis V, Karakiewicz P, Montorsi F, Kikuchi E, Zigeuner R, Weizer A, Bolenz C, Bensalah K, Suardi N, Raman JD, Lotan Y, Waldert M, Ng CK, Fernandez M, Koppie TM, Strobel P, Kabbani W, Murai M, Langner C, Roscigno M, Wheat J, Guo CC, Wood CG, Shariat SF (2009) Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 103(3):307–311. doi: 10.1111/j.1464-410X.2008.08003.x PubMedCrossRefGoogle Scholar
  8. 8.
    Pieras E, Frontera G, Ruiz X, Vicens A, Ozonas M, Piza P (2010) Concomitant carcinoma in situ and tumour size are prognostic factors for bladder recurrence after nephroureterectomy for upper tract transitional cell carcinoma. BJU Int 106(9):1319–1323. doi: 10.1111/j.1464-410X.2010.09341.x PubMedCrossRefGoogle Scholar
  9. 9.
    Wheat JC, Weizer AZ, Wolf JS Jr, Lotan Y, Remzi M, Margulis V, Wood CG, Montorsi F, Roscigno M, Kikuchi E, Zigeuner R, Langner C, Bolenz C, Koppie TM, Raman JD, Fernandez M, Karakiewizc P, Capitanio U, Bensalah K, Patard JJ, Shariat SF (2010) Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy. Urol Oncol. doi: 10.1016/j.urolonc.2010.01.001
  10. 10.
    Roupret M, Fromont G, Azzouzi AR, Catto JW, Vallancien G, Hamdy FC, Cussenot O (2005) Microsatellite instability as predictor of survival in patients with invasive upper urinary tract transitional cell carcinoma. Urology 65(6):1233–1237. doi: 10.1016/j.urology.2005.01.019 PubMedCrossRefGoogle Scholar
  11. 11.
    Eltz S, Comperat E, Cussenot O, Roupret M (2008) Molecular and histological markers in urothelial carcinomas of the upper urinary tract. BJU Int 102(5):532–535. doi: 10.1111/j.1464-410X.2008.07659.x PubMedCrossRefGoogle Scholar
  12. 12.
    Kelly RJ, Lopez-Chavez A, Citrin D, Janik JE, Morris JC (2011) Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer 10:35. doi: 10.1186/1476-4598-10-35 PubMedCrossRefGoogle Scholar
  13. 13.
    Fortugno P, Wall NR, Giodini A, O’Connor DS, Plescia J, Padgett KM, Tognin S, Marchisio PC, Altieri DC (2002) Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J Cell Sci 115(Pt 3):575–585PubMedGoogle Scholar
  14. 14.
    Li F, Yang J, Ramnath N, Javle MM, Tan D (2005) Nuclear or cytoplasmic expression of survivin: what is the significance? Int J Cancer 114(4):509–512. doi: 10.1002/ijc.20768 PubMedCrossRefGoogle Scholar
  15. 15.
    Marioni G, Ottaviano G, Marchese-Ragona R, Giacomelli L, Bertolin A, Zanon D, Marino F, Staffieri A (2006) High nuclear expression of the apoptosis inhibitor protein survivin is associated with disease recurrence and poor prognosis in laryngeal basaloid squamous cell carcinoma. Acta Otolaryngol 126(2):197–203. doi: 10.1080/00016480500266685 PubMedCrossRefGoogle Scholar
  16. 16.
    Preuss SF, Weinell A, Molitor M, Stenner M, Semrau R, Drebber U, Weissenborn SJ, Speel EJ, Wittekindt C, Guntinas-Lichius O, Hoffmann TK, Eslick GD, Klussmann JP (2008) Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer. Br J Cancer 98(3):627–632. doi: 10.1038/sj.bjc.6604192 PubMedCrossRefGoogle Scholar
  17. 17.
    Qi G, Kudo Y, Ando T, Tsunematsu T, Shimizu N, Siriwardena SB, Yoshida M, Keikhaee MR, Ogawa I, Takata T (2010) Nuclear survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B. Oral Oncol 46(4):263–270. doi: 10.1016/j.oraloncology.2010.01.004 PubMedCrossRefGoogle Scholar
  18. 18.
    Erpolat OP, Gocun PU, Akmansu M, Karakus E, Akyol G (2012) High expression of nuclear survivin and Aurora B predicts poor overall survival in patients with head and neck squamous cell cancer. Strahlenther Onkol 188(3):248–254. doi: 10.1007/s00066-011-0042-7 PubMedCrossRefGoogle Scholar
  19. 19.
    Moon WS, Tarnawski AS (2003) Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth? Hum Pathol 34(11):1119–1126PubMedCrossRefGoogle Scholar
  20. 20.
    Fields AC, Cotsonis G, Sexton D, Santoianni R, Cohen C (2004) Survivin expression in hepatocellular carcinoma: correlation with proliferation, prognostic parameters, and outcome. Mod Pathol 17(11):1378–1385. doi: 10.1038/modpathol.3800203 PubMedCrossRefGoogle Scholar
  21. 21.
    Grabowski P, Kuhnel T, Muhr-Wilkenshoff F, Heine B, Stein H, Hopfner M, Germer CT, Scherubl H (2003) Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma. Br J Cancer 88(1):115–119. doi: 10.1038/sj.bjc.6600696 PubMedCrossRefGoogle Scholar
  22. 22.
    Mega S, Miyamoto M, Li L, Kadoya M, Takahashi R, Hase R, Kaneko H, Shichinohe T, Kawarada Y, Itoh T, Morikawa T, Kondo S (2006) Immunohistochemical analysis of nuclear survivin expression in esophageal squamous cell carcinoma. Dis Esophagus 19(5):355–359. doi: 10.1111/j.1442-2050.2006.00604.x PubMedCrossRefGoogle Scholar
  23. 23.
    Piras F, Murtas D, Minerba L, Ugalde J, Floris C, Maxia C, Colombari R, Perra MT, Sirigu P (2007) Nuclear survivin is associated with disease recurrence and poor survival in patients with cutaneous malignant melanoma. Histopathology 50(7):835–842. doi: 10.1111/j.1365-2559.2007.02695.x PubMedCrossRefGoogle Scholar
  24. 24.
    Xie D, Zeng YX, Wang HJ, Wen JM, Tao Y, Sham JS, Guan XY (2006) Expression of cytoplasmic and nuclear survivin in primary and secondary human glioblastoma. Br J Cancer 94(1):108–114. doi: 10.1038/sj.bjc.6602904 PubMedCrossRefGoogle Scholar
  25. 25.
    Kim J, McNiff JM (2008) Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma. Mod Pathol 21(6):764–769. doi: 10.1038/modpathol.2008.61 PubMedCrossRefGoogle Scholar
  26. 26.
    Shariat SF, Ashfaq R, Karakiewicz PI, Saeedi O, Sagalowsky AI, Lotan Y (2007) Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer 109(6):1106–1113. doi: 10.1002/cncr.22521 PubMedCrossRefGoogle Scholar
  27. 27.
    Shariat SF, Karakiewicz PI, Godoy G, Karam JA, Ashfaq R, Fradet Y, Isbarn H, Montorsi F, Jeldres C, Bastian PJ, Nielsen ME, Muller SC, Sagalowsky AI, Lotan Y (2009) Survivin as a prognostic marker for urothelial carcinoma of the bladder: a multicenter external validation study. Clin Cancer Res 15(22):7012–7019. doi: 10.1158/1078-0432.CCR-08-2554 PubMedCrossRefGoogle Scholar
  28. 28.
    Karam JA, Lotan Y, Ashfaq R, Sagalowsky AI, Shariat SF (2007) Survivin expression in patients with non-muscle-invasive urothelial cell carcinoma of the bladder. Urology 70(3):482–486. doi: 10.1016/j.urology.2007.05.009 PubMedCrossRefGoogle Scholar
  29. 29.
    Yin W, Chen N, Zhang Y, Zeng H, Chen X, He Y, Wang X, Zhou Q (2006) Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder. Mod Pathol 19(11):1487–1497. doi: 10.1038/modpathol.3800675 PubMedGoogle Scholar
  30. 30.
    Skagias L, Politi E, Karameris A, Sambaziotis D, Archondakis A, Ntinis A, Moreas I, Vasou O, Koutselini H, Patsouris E (2009) Survivin expression as a strong indicator of recurrence in urothelial bladder cancer. Predictive value of nuclear versus cytoplasmic staining. Anticancer Res 29(10):4163–4167PubMedGoogle Scholar
  31. 31.
    Okada E, Murai Y, Matsui K, Isizawa S, Cheng C, Masuda M, Takano Y (2001) Survivin expression in tumor cell nuclei is predictive of a favorable prognosis in gastric cancer patients. Cancer Lett 163(1):109–116PubMedCrossRefGoogle Scholar
  32. 32.
    Qi G, Tuncel H, Aoki E, Tanaka S, Oka S, Kaneko I, Okamoto M, Tatsuka M, Nakai S, Shimamoto F (2009) Intracellular localization of survivin determines biological behavior in colorectal cancer. Oncol Rep 22(3):557–562PubMedGoogle Scholar
  33. 33.
    Kleinberg L, Florenes VA, Silins I, Haug K, Trope CG, Nesland JM, Davidson B (2007) Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma. Cancer 109(2):228–238. doi: 10.1002/cncr.22426 PubMedCrossRefGoogle Scholar
  34. 34.
    Felisiak-Golabek A, Rembiszewska A, Rzepecka IK, Szafron L, Madry R, Murawska M, Napiorkowski T, Sobiczewski P, Osuch B, Kupryjanczyk J (2011) Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients. J Ovarian Res 4(1):20. doi: 10.1186/1757-2215-4-20 PubMedCrossRefGoogle Scholar
  35. 35.
    Vischioni B, van der Valk P, Span SW, Kruyt FA, Rodriguez JA, Giaccone G (2004) Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer. Ann Oncol 15(11):1654–1660. doi: 10.1093/annonc/mdh436 PubMedCrossRefGoogle Scholar
  36. 36.
    Shinohara ET, Gonzalez A, Massion PP, Chen H, Li M, Freyer AS, Olson SJ, Andersen JJ, Shyr Y, Carbone DP, Johnson DH, Hallahan DE, Lu B (2005) Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma. Cancer 103(8):1685–1692. doi: 10.1002/cncr.20951 PubMedCrossRefGoogle Scholar
  37. 37.
    Nakanishi K, Tominaga S, Hiroi S, Kawai T, Aida S, Kasamatsu H, Aurues T, Hayashi T, Ikeda T (2002) Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. Virchows Arch 441(6):559–563. doi: 10.1007/s00428-002-0712-z PubMedCrossRefGoogle Scholar
  38. 38.
    Jeong IG, Kim SH, Jeon HG, Kim BH, Moon KC, Lee SE, Lee E (2009) Prognostic value of apoptosis-related markers in urothelial cancer of the upper urinary tract. Hum Pathol 40(5):668–677. doi: 10.1016/j.humpath.2008.10.010 PubMedCrossRefGoogle Scholar
  39. 39.
    Li F (2005) Role of survivin and its splice variants in tumorigenesis. Br J Cancer 92(2):212–216. doi: 10.1038/sj.bjc.6602340 PubMedGoogle Scholar
  40. 40.
    Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T, Inuzuka M (2004) Identification of a novel splice variant of the human anti-apoptopsis gene survivin. Biochem Biophys Res Commun 314(3):902–907PubMedCrossRefGoogle Scholar
  41. 41.
    Chaopotong P, Kajita S, Hashimura M, Saegusa M (2012) Nuclear survivin is associated with cell proliferative advantage in uterine cervical carcinomas during radiation therapy. J Clin Pathol 65(5):424–430. doi: 10.1136/jclinpath-2011-200477 PubMedCrossRefGoogle Scholar
  42. 42.
    Nouraee N, Mowla SJ, Ozhand A, Parvin M, Ziaee SA, Hatefi N (2009) Expression of survivin and its spliced variants in bladder tumors as a potential prognostic marker. Urol J 6(2):101–108PubMedGoogle Scholar
  43. 43.
    Lehmann J, Suttmann H, Kovac I, Hack M, Kamradt J, Siemer S, Wullich B, Zwergel U, Stockle M (2007) Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol 51(5):1281–1288. doi: 10.1016/j.eururo.2006.11.021 PubMedCrossRefGoogle Scholar
  44. 44.
    Li CC, Chang TH, Wu WJ, Ke HL, Huang SP, Tsai PC, Chang SJ, Shen JT, Chou YH, Huang CH (2008) Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Eur Urol 54(5):1127–1134. doi: 10.1016/j.eururo.2008.01.054 PubMedCrossRefGoogle Scholar
  45. 45.
    Li WM, Li CC, Ke HL, Wu WJ, Huang CN, Huang CH (2009) The prognostic predictors of primary ureteral transitional cell carcinoma after radical nephroureterectomy. J Urol 182(2):451–458. doi: 10.1016/j.juro.2009.04.026, discussion 458PubMedCrossRefGoogle Scholar
  46. 46.
    Chromecki TF, Bensalah K, Remzi M, Verhoest G, Cha EK, Scherr DS, Novara G, Karakiewicz PI, Shariat SF (2011) Prognostic factors for upper urinary tract urothelial carcinoma. Nat Rev Urol 8(8):440–447. doi: 10.1038/nrurol.2011.96 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Hiroshi Kitamura
    • 1
    Email author
  • Toshihiko Torigoe
    • 2
  • Yoshihiko Hirohashi
    • 2
  • Hiroko Asanuma
    • 2
  • Ryuta Inoue
    • 1
  • Sachiyo Nishida
    • 1
  • Toshiaki Tanaka
    • 1
  • Naoya Masumori
    • 1
  • Noriyuki Sato
    • 2
  • Taiji Tsukamoto
    • 1
  1. 1.Department of Urology, School of MedicineSapporo Medical UniversitySapporoJapan
  2. 2.Department of Pathology, School of MedicineSapporo Medical UniversitySapporoJapan

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