Sacit Nuri GÖRGEL, Uğur BALCI, Murat ERMETE, Ertuğrul ŞEFİK, Fatma Seher PEHLİVAN, Yelda MORGÜL, Ayşegül SARI

Relationship of cox-2, bax, bcl-2, ki67, p53 expression to clinicopathologic parameters and their impact on prognosis in renal cell carcinoma

Giriş ve Amaç : Renal Hücreli Karsinom (RHK), böbrek korteksinden kaynaklanan bir malignite olup malign böbrek tümörlerinin %85 inioluşturmaktadır. Günümüzde RHK lu hastalarda prognozun en önemli belirleyicileri olarak evre ve nükleer derece kabul edilmektedir.Bununla birlikte pek çok hastada evreleme ve dereceleme hastalığın seyrinin belirlenmesinde yetersiz kalmaktadır. Prognozu öngörülemeyen bu hastaların belirlenmesi onkolojik açıdan önemlidir. Bu nedenle tümörün davranışının belirlenmesi amacıyla ekparametrelere ihtiyaç vardır. Bu çalışmada RHK da Cox-2, Bax, Bcl-2, p53 ekspresyonu ve Ki-67 proliferasyon indeksinin histopatolojikparametreler ile ilişkisini ve prognoza etkisini araştırmayı amaçladık.Gereç ve Yöntem : Çalışmaya İzmir Atatürk Eğitim ve Araştırma Hastanesi Patoloji bölümüne Mayıs 1998 - Mayıs 2008 tarihleri arasında 1.Üroloji kliniğinden gönderilen 70 adet RHK olgusu dahil edildi. Çalışmada, tümör çapı, tümörün histolojik tipi, nükleer derecesi, evresi,metastaz durumu ve hasta yaşam süresi ile immunohistokimyasal olarak uygulanan Bax, Cox-2, Bcl-2, p53 ve Ki 67 ekspresyonununboyanma yüzdeleri istatiksel olarak karşılaştırıldı.Bulgular: Çalışmamızda bu belirteçler ile prognoz dahil hiçbir klinikopatolojik parametre arasında anlamlı ilişki bulunmadı. Sonuç: Tümörün patolojik evresi sadece metastaz gelişimini öngörmede istatiksel anlamalılık göstermiş olup sağ kalımı belirlemede etkisizkalmıştır. RHK da Cox-2 ekspresyonu, Bax, Bcl-2 ve p53 gibi apoptik belirteçler ve Ki67 proliferasyon indeksinin prognoz üzerine etkisininolup olmadığını net olarak belirleyebilmek için standardize edilmiş yöntemlerle, daha fazla sayıda olgu ve takip süresi içeren çalışmalaraihtiyaç olduğunu düşünmekteyiz.

Renal hücreli karsinomlarda cox-2, bax, bcl-2, ki-67 ve p53 ekspresyonunun klinikopatolojik parametrelerle ilişkisi ve prognoza etkisi

Objective: Renal cell carcinoma (RCC) is a malignancy originating from the renal cortex and is accounted for 85% of all malignant kidneytumors. Currently, tumor stage and nuclear grade are recognized as the most important determinants of prognosis in patients with RCC.Nonetheless, staging and grading do not suffice for predicting the prognosis in many patients. However, determining such patients bearsimportance in terms of oncology. Therefore, additional parameters are required to define the tumor behavior. In this study, we aimed toinvestigate the relation of Cox-2, Bax, Bcl-2, and p53 expression, as well as Ki-67 proliferation index to histopathologic parameters, andtheir impact on prognosis.Material and Methods: Our study included 70 RCC patients who were referred to the Pathology Department of Izmir Ataturk Teachingand Research Hospital from the First Urology Clinic between May 1998 and May 2008. The data including tumor diameter, histologic tumortype, nuclear grade, tumor stage, metastatic status, life expectancy of patients as well as staining percentages of Bax, Cox-2, Bcl-2, p53,and Ki-67 were compared.Results: In this study, no relationship was found between those markers and clinicopathologic parameters including the prognosis.Conclusion: Tumor pathologic stage showed a statistically significant predictive value for metastasis development, however, it failed topredict survival. There is a need for studies including standardized methods, larger samples, and longer follow-up periods in order to revealeffects of Cox-2, Bax, Bcl-2, P53 markers, and Ki-67 proliferation index on prognosis.

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1. Eble JN SG, Epstein JI, Sesterhenn IA, , editor. World Health Organization Classification of Tumours. Lyon: IARC Press 2004.
2. Rodriguez R, Fishman EK, Marshall FF. Differential diagnosis and evaluation of the incidentally discovered renal mass. Semin Urol Oncol 1995;13:246-53.
3. Delahunt B. Histopathologic prognostic indicators for renal cell carcinoma. Semin Diagn Pathol 1998;15:68-76.
4. Cho DS, Joo HJ, Oh DK, Kang JH, Kim YS, Lee KB, et al. Cyclooxygenase-2 and p53 ekspression as prognostic indicators in conventional renal cell carcinoma. Yonsei Med J 2005;28;46:133-40.
5. Masunaga R, Kohno H, Dhar DK, Ohno S, Shibakita M, Kinugasa S, et al. Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res 2000;6:4064- 8.
6. Joo YE, Rew JS, Seo YH, Choi SK, Kim YJ, Park CS, et al. Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer. J Clin Gastroenterol 2003;37:28-33.
7. Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 2003;15;97:2978-87.
8. Chen YJ, Wang LS, Wang PH, Lai CR, Yen MS, Ng HT, et al. High cyclooxygenase-2 expression in cervical adenocarcinomas. Gynecol Oncol 2003;88:379-85.
9. Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001;7:861-7.
10. Yoshimura R, Sano H, Masuda C, Kawamura M, Tsubouchi Y, Chargui J, et al. Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 2000;1;89:589-96.
11. Shirahama T. Cyclooxygenase-2 expression is up-regulated in transitional cell carcinoma and its preneoplastic lesions in the human urinary bladder. Clin Cancer Res 2000;6:2424-30.
12. Miyata Y, Koga S, Kanda S, Nishikido M, Hayashi T, Kanetake H. Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival. Clin Cancer Res 2003;9:1741-9.
13. Ronkainen H, Vaarala MH, Hirvikoski P, Ristimaki A. HuR expression is a marker of poor prognosis in renal cell carcinoma. Tumour Biol 2011;32:481-7.
14. Kankuri-Tammilehto MK, Soderstrom KO, Pelliniemi TT, Vahlberg T, Pyrhonen SO, Salminen EK. Prognostic evaluation of COX-2 expression in renal cell carcinoma. Anticancer Res 2010;30:3023-30.
15. Yoshimura R, Matsuyama M, Kawahito Y, Tsuchida K, Kuratsukuri K, Takemoto Y, et al. Study of cyclooxygenase-2 in renal cell carcinoma. Int J Mol Med 2004;13:229-33.
16. Dirim A, Haberal AN, Goren MR, Tekin MI, Peskircioglu L, Demirhan B, et al. VEGF, COX-2, and PCNA expression in renal cell carcinoma subtypes and their prognostic value. Int Urol Nephrol 2008;40:861-8.
17. Tuna B, Yorukoglu K, Gurel D, Mungan U, Kirkali Z. Significance of COX-2 expression in human renal cell carcinoma. Urology 2004;64:1116-20.
18. Kallio JP, Hirvikoski P, Helin H, Luukkaala T, Tammela TL, Kellokumpu-Lehtinen P, et al. Renal cell carcinoma MIB-1, Bax and Bcl-2 expression and prognosis. J Urol 2004;172:2158-61.
19. Vasavada SP, Novick AC, Williams BR. P53, bcl-2, and Bax expression in renal cell carcinoma. Urology 1998;51:1057- 61.
20. Rioux-Leclercq N, Turlin B, Bansard J, Patard J, Manunta A, Moulinoux JP, et al. Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. Urology 2000;55:501-5.
21. de Riese WT, Crabtree WN, Allhoff EP, Werner M, Liedke S, Lenis G, et al. Prognostic significance of Ki-67 immunostaining in nonmetastatic renal cell carcinoma. J Clin Oncol 1993;11:1804-8.
22. Yildiz E, Gokce G, Kilicarslan H, Ayan S, Goze OF, Gultekin EY. Prognostic value of the expression of Ki-67, CD44 and vascular endothelial growth factor, and microvessel invasion, in renal cell carcinoma. BJU Int 2004;93:1087-93.
23. Greene FL PD, Fleming ID., editor. American Cancer Joint Committee on Cancer in AJCC, Cancer Staging Manuel. Philedelphia: Lipincott-Raven; 2002.
24. Koga S, Nishikido M, Hayashi T, Matsuya F, Saito Y, Kanetake H. Outcome of surgery in cystic renal cell carcinoma. Urology 2000;56:67-70.
25. Kirkali Z, Yorukoglu K, Ozkara E, Kazimoglu H, Mungan U. Proliferative activity, angiogenesis and nuclear morphometry in renal cell carcinoma. Int J Urol 2001;8:697- 703.
26. Khan Z, Khan N, Tiwari RP, Sah NK, Prasad GB, Bisen PS. Biology of Cox-2: an application in cancer therapeutics. Curr Drug Targets 2011;12:1082-93.
27. Chen Q, Shinohara N, Abe T, Watanabe T, Nonomura K, Koyanagi T. Significance of COX-2 expression in human renal cell carcinoma cell lines. Int J Cancer 2004;1;108:825- 32.
28. Lee JW, Park JH, Suh JH, Nam KH, Choe JY, Jung HY, et al. Cyclooxygenase-2 expression and its prognostic significance in clear cell renal cell carcinoma. Korean J Pathol 2012;46:237-45.
29. Hashimoto Y, Kondo Y, Kimura G, Matsuzawa I, Sato S, Ishizaki M, et al. Cyclooxygenase-2 expression and relationship to tumour progression in human renal cell carcinoma. Histopathology 2004;44:353-9.
30. Ye D, Li H, Qian S, Sun Y, Zheng J, Ma Y. bcl-2/bax expression and p53 gene status in human bladder cancer: relationship to early recurrence with intravesical chemotherapy after resection. J Urol 1998;160:2025-8; discussion 9.
31. Sejima T, Miyagawa I. Expression of bcl-2, p53 oncoprotein, and proliferating cell nuclear antigen in renal cell carcinoma. Eur Urol 1999;35:242-8.
32. Moch H, Sauter G, Gasser TC, Buchholz N, Bubendorf L, Richter J, et al. p53 protein expression but not mdm-2 protein expression is associated with rapid tumor cell proliferation and prognosis in renal cell carcinoma. Urol Res 1997;25 Suppl 1:S25-30.
33. Oda H, Nakatsuru Y, Ishikawa T. Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 1995;1;55:658-62.
34. Reiter RE, Anglard P, Liu S, Gnarra JR, Linehan WM. Chromosome 17p deletions and p53 mutations in renal cell carcinoma. Cancer Res 1993; 1;53:3092-7.
35. Uhlman DL, Nguyen PL, Manivel JC, Aeppli D, Resnick JM, Fraley EE, et al. Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. J Natl Cancer Inst 1994; 5;86:1470-5.
36. Oudard S, Levalois C, Andrieu JM, Bougaran J, Validire P, Thiounn N, et al. Expression of genes involved in chemoresistance, proliferation and apoptosis in clinical samples of renal cell carcinoma and correlation with clinical outcome. Anticancer Res 2002;22:121-8.
37. Huang A, Fone PD, Gandour-Edwards R, White RW, Low RK. Immunohistochemical analysis of BCL-2 protein expression in renal cell carcinoma. J Urol 1999;162:610-3.
38. Uzunlar AK, Sahin H, Yilmaz F, Ozekinci S. Expression of p53 oncoprotein and bcl-2 in renal cell carcinoma. Saudi Med J 2005;26:37-41.
39. Hofmockel G, Wittmann A, Dammrich J, Bassukas ID. Expression of p53 and bcl-2 in primary locally confined renal cell carcinomas: no evidence for prognostic significance. Anticancer Res 1996;16:3807-11.
40. Lipponen P, Eskelinen M, Syrjanen K. Expression of tumour- suppressor gene Rb, apoptosis-suppressing protein Bcl-2 and c-Myc have no independent prognostic value in renal adenocarcinoma. Br J Cancer 1995;71:863-7.
41. Pammer J, Exner M, Regele H, Haitel A, Weninger W, Horvat R, et al. Expression of bcl-2, bcl-x, bax and bak in renal parenchyma, oncocytomas and renal cell carcinomas. Pathol Res Pract 1998;194:837-45.
42. Dudderidge TJ, Stoeber K, Loddo M, Atkinson G, Fanshawe T, Griffiths DF, et al. Mcm2, Geminin, and KI67 define proliferative state and are prognostic markers in renal cell carcinoma. Clin Cancer Res 2005;1;11:2510-7.
43. Papadopoulos I, Weichert-Jacobsen K, Wacker HH, Sprenger E. Correlation between DNA ploidy, proliferation marker Ki-67 and early tumor progression in renal cell carcinoma. A prospective study. Eur Urol 1997;31:49-53.
44. Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K. Prognostic value of Ki-67 expression in renal cell carcinomas. Eur Urol 1997;31:350-5.