Tumor Biology

, Volume 36, Issue 11, pp 8471–8478 | Cite as

The impact of immunohistochemical staining with ezrin-carbonic anhydrase IX and neuropilin-2 on prognosis in patients with metastatic renal cell cancer receiving tyrosine kinase inhibitors

  • Bulent Cetin
  • Ipek Isık Gonul
  • Suleyman Buyukberber
  • Barıs Afsar
  • Ozge Gumusay
  • Efnan Algın
  • Nedim Turan
  • Ahmet Ozet
  • Mustafa Benekli
  • Ugur Coskun
Research Article

Abstract

The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. In this retrospective study, we evaluated the prognostic role of carbonic anhydrase-IX, ezrin, and neuropilin in metastatic RCC patients. The expression of several biomarkers were measured by immunohistochemistry (IHC) in 45 patients with advanced stage RCC treated with second-line tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) after failure of interferon-alpha between January 2007 and June 2012. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on the survival. Age, ezrin and neuropilin-2 overexpression were found to be statistically significant factors (P < 0.05) for PFS in the univariate analysis. Ezrin and neuropilin-2 overexpression, hemoglobin and albumin level were statistically significant factors (P < 0.05) for OS in the univariate analysis. Multivariate analysis revealed that low expression of ezrin and neuropilin-2 was an independent prognostic factor for PFS and OS. The median PFS was 4 months for patients overexpressing neuropilin-2 versus 11 months for those with lower expression of neuropilin-2 (p = 0.033). The median OS was longer in patients with low levels of neuropilin-2 expression (26 months) compared to patients overexpressing neuropilin-2 (13 months) (p = 0.023). Increased expression of ezrin was associated with poor prognosis in patients treated with TKIs targeting VEGF (PFS, 3 vs 7 months; p = 0.012). High ezrin expression was associated with shorter OS (p = 0.009). This is the first study in the literature showing that neuropilin-2 and ezrin are related with prognosis in patients with advanced RCC.

Keywords

Advanced renal cell carcinoma Molecular markers Targeted drugs Prognostic factors 

Notes

Conflicts of interest

None

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2009;59:225–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170:2163–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Cohen HT, McGovern FJ. Medical progress: renal-cell carcinoma. N Engl J Med. 2005;353:2477–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Novick AC. Kidney cancer: past, present and future. Urol Oncol. 2007;25:188–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373:1119–32.CrossRefPubMedGoogle Scholar
  6. 6.
    Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol. 2000;163(2):408–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Bukowski RM. Cytokine therapy for metastatic renal cell carcinoma. Semin Urol Oncol. 2001;19(2):148–54.PubMedGoogle Scholar
  8. 8.
    Rini B. Vascular endothelial growth factor targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res. 2007;13(4):1098–106.CrossRefPubMedGoogle Scholar
  9. 9.
    Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 2001;158:905–19.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9:802–11.PubMedGoogle Scholar
  11. 11.
    Leibovich BC, Sheinin Y, Lohse CM, Thompson RH, Cheville JC, Zavada J, et al. Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol. 2007;25(30):4757–64.CrossRefPubMedGoogle Scholar
  12. 12.
    Hiscox S, Jiang WG. Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin/beta-catenin. J Cell Sci. 1999;112(18):3081–90.PubMedGoogle Scholar
  13. 13.
    Gray MJ, Van Buren G, Dallas NA, Xia L, Wang X, Yang AD, et al. Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J Natl Cancer Inst. 2008;100:109–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Bui MH, Zisman A, Pantuck AJ, Han KR, Wieder J, Belldegrun AS. Prognostic factors and molecular markers for renal cell carcinoma. Expert Rev Anticancer Ther. 2001;1(4):565–75.CrossRefPubMedGoogle Scholar
  15. 15.
    Han KR, Pantuck AJ, Belldegrun AS. Basic biology and clinical behavior of renal cell carcinoma. Kidney Cancer. 2003; 67-89.Google Scholar
  16. 16.
    Crispen PL, Boorjian SA, Lohse CM, Leibovich BC, Kwon ED. Predicting disease progression after nephrectomy for localized renal cell carcinoma: the utility of prognostic models and molecular biomarkers. Cancer. 2008;113:450–60.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Parker AS, Leibovich BC, Lohse CM, Sheinin Y, Kuntz SM, Eckel-Passow JE, et al. Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma. Cancer. 2009;115(10):2092–103.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bui MH, Visapaa H, Seligson D, Kim H, Han KR, Huang Y, et al. Prognostic value of carbonic anhydrate IX and Ki67 as predictors of survival for renal clear cell carcinoma. J Urol. 2004;171:2461–66.CrossRefPubMedGoogle Scholar
  19. 19.
    Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res. 2005;11:3714–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Cho D, Signoretti S, Dabora S, Regan M, Seeley A, Mariotti M, et al. Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2007;5:379–85.CrossRefPubMedGoogle Scholar
  21. 21.
    Choueiri TK, Cheng S, Qu AQ, Pastorek J, Atkins MB, Signoretti S. Carbonic anhydrase IX as potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: Analysis from the treatment approaches in renal cancer global evaluaion trial (TARGET).Urol Oncol. 2012Google Scholar
  22. 22.
    Weng WH, Ahlén J, Aström K, Lui WO, Larsson C. Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue esarcomas. Clin Cancer Res. 2005;11:6198–204.CrossRefPubMedGoogle Scholar
  23. 23.
    Zeng H, Xu L, Xiao D, Zhang H, Wu X, Zheng R, et al. Altered expression of ezrin in esophageal squamous cell carcinoma. J Histochem Cytochem. 2006;54:889–96.CrossRefPubMedGoogle Scholar
  24. 24.
    Bal N, Yildirim S, Nursal TZ, Bolat F, Kayaselcuk F. Association of ezrin expression in intestinal and diffuse gastric carcinoma with clinicopathological parameters and tumor type. World J Gastroenterol. 2007;13:3726–729.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Köbel M, Langhammer T, Hüttelmaier S, Schmitt WD, Kriese K, Dittmer J, et al. Ezrin expression is related to poor prognosis in FIGO stage I endometrial carcinomas. Mod Pathol. 2006;19:581–87.CrossRefPubMedGoogle Scholar
  26. 26.
    Köbel M, Gradhand E, Zeng K, Schmitt WD, Kriese K, Lantzsch T, et al. Ezrin promotes ovarian carcinoma cell invasion and its retained expression predicts poor prognosis in ovarian carcinoma. Int J Gynecol Pathol. 2006;25:121–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Elliott BE, Meens JA, SenGupta SK, Louvard D, Arpin M. The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells. Breast Cancer Res. 2005;7:365–73.CrossRefGoogle Scholar
  28. 28.
    Zhang XQ, Chen GP, Wu T, Yan JP, Zhou JY. Expression and clinical significance of ezin in non-small-cell lung cancer. Clin Lung Cancer. 2012;13(3):196–204.CrossRefPubMedGoogle Scholar
  29. 29.
    Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2:573–83.CrossRefPubMedGoogle Scholar
  30. 30.
    Yasuoka H, Nakamura Y, Zuo H, Tang W, Takamura Y, Miyauchi A, et al. VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma. Mod Pathol. 2005;18:1127–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Nakamura Y, Yasuoka H, Zuo H, Takamura Y, Miyauchi A, Nakamura M, et al. Nitric oxide in papillary thyroid carcinoma: induction of vascular endothelial growth factor d and correlation with lymph node metastasis. J Clin Endocrinol Metab. 2006;91:1582–85.CrossRefPubMedGoogle Scholar
  32. 32.
    Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL, et al. High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum Pathol. 2008;39:1835–43.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Bulent Cetin
    • 1
  • Ipek Isık Gonul
    • 2
  • Suleyman Buyukberber
    • 3
  • Barıs Afsar
    • 4
  • Ozge Gumusay
    • 3
  • Efnan Algın
    • 5
  • Nedim Turan
    • 6
  • Ahmet Ozet
    • 3
  • Mustafa Benekli
    • 3
  • Ugur Coskun
    • 3
  1. 1.Department of Internal Medicine, Division of Medical OncologyVan Education and Research HospitalEdremitTurkey
  2. 2.Department of PathologyGazi University Faculty of MedicineAnkaraTurkey
  3. 3.Department of Internal Medicine, Division of Medical OncologyGazi University Faculty of MedicineAnkaraTurkey
  4. 4.Department of Internal Medicine, Division of NephrologyKonya Numune State HospitalKonyaTurkey
  5. 5.Department of Internal Medicine, Division of Medical OncologyAnkara Numune Education and Research HospitalAnkaraTurkey
  6. 6.Department of Internal Medicine, Division of Medical OncologyCumhuriyet University Faculty of MedicineSivasTurkey

Personalised recommendations