Prognostic Factors of Prostate Cancer in Tunisian Men: Immunohistochemical Study

  • Missaoui, Nabiha (Research Unit UR14ES17, Cancer Epidemiology and Cytopathology in Tunisian Center, Medecine Faculty of Sousse, University of Sousse) ;
  • Abdelkarim, Soumaya Ben (Pathology Department, Farhet Hached Hospital) ;
  • Mokni, Moncef (Pathology Department, Farhet Hached Hospital) ;
  • Hmissa, Sihem (Research Unit UR14ES17, Cancer Epidemiology and Cytopathology in Tunisian Center, Medecine Faculty of Sousse, University of Sousse)
  • Published : 2016.05.01


Background: Prostate cancer is the second most common male cancer and remains a leading cause of cancer death worldwide. Heterogeneity regarding recurrence, tumor progression and therapeutic response reflects the inadequacy of traditional prognostic factors and underlies interest in new genetic and molecular markers. In this work, we studied the prognostic value of the expression of 9 proteins, Ki-67, p53, Bcl-2, PSA, HER2, E-cadherin, $p21^{WAF1/Cip1}$, $p27^{Kip1}$ and $p16^{ink4a}$ in prostate cancer. Materials and Methods: We conducted a retrospective study of 50 prostate cancers diagnosed in Pathology Department of Farhet Hached Hospital, Sousse, Tunisia, during a period of 12 months. Clinico-pathological data and survival were investigated. Protein expression was analyzed by immunohistochemistry on archived material. Results: Expression or over-expression of Ki-67, p53, Bcl-2, PSA, HER2, E-Cadherin, $p21^{WAF1/Cip1}$, $p27^{Kip1}$ and $p16^{ink4a}$ was observed in 68%, 24%, 32%, 78%, 12%, 90%, 20%, 44% and 56% of cases, respectively. Overall five-year survival was 68%. A statistically significant correlation was observed between death occurrence and advanced age (p=0.018), degree of tumor differentiation (p=0.0001), perineural invasion (p=0.016) and metastasis occurrence (p=0.05). Death occurrence was significantly correlated with the expression of p53 (p=0.007), Bcl-2 (p=0.02), Ki-67 (p=0.05) and $p27^{Kip1}$ (p=0.04). Conclusions: The p53, Bcl-2, Ki-67 and $p27^{Kip1}$ proteins may be useful additional prognostic markers for prostate cancer. The use of these proteins in clinical practice can improve prognosis prediction, disease screening and treatment response of prostatic cancer.


Prostate cancer;prognosis;markers;immunohistochemistry


  1. Aghaei M, Panjehpour M, Karami-Tehrani F, et al (2011). Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway. J Cancer Res Clin Oncol, 137, 1511-23.
  2. Baade PD, Yu XQ, Smith DP, et al (2015). Geographic disparities in prostate cancer outcomes--review of international patterns. Asian Pac J Cancer Prev, 16, 1259-75.
  3. Bachmann HS, Heukamp LC, Schmitz KJ, et al (2011). Regulatory BCL2 promoter polymorphism (-938C>A). is associated with adverse outcome in patients with prostate carcinoma. Int J Cancer, 129, 2390-9.
  4. Bantis A, Giannopoulos A, Gonidi M, et al (2004). Expression of p120, Ki-67 and PCNA as proliferation biomarkers in imprint smears of prostate carcinoma and their prognostic value. Cytopathology, 15, 25-31.
  5. Bashir MN (2015). Epidemiology of Prostate Cancer. Asian Pac J Cancer Prev, 16, 5137-41.
  6. Bauer JJ, Sesterhenn IA, Mostofi FK, et al (1996). Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer. J Urol, 156, 1511-6.
  7. Bensalah K, Lotan Y, Karam JA et al (2008). New circulating biomarkers for prostate cancer. Prostate Cancer Prostatic Dis, 11, 112-20.
  8. Berney DM, Gopalan A, Kudahetti S, et al (2009). Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study. Br J Cancer, 100, 888-93.
  9. Bostrom PJ, Bjartell AS, Catto JW, et al (2015). Genomic predictors of outcome in prostate cancer. Eur Urol, 68, 1033-44.
  10. Calvo BF, Levine AM, Marcos M, et al (2003). Human epidermal receptor-2 expression in prostate cancer. Clin Cancer Res, 9, 1087-97.
  11. Chuang AY, DeMarzo AM, Veltri RW, et al (2007). Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. Am J Surg Pathol, 31, 1246-55.
  12. Concato J, Jain D, Uchio E, et al (2009). Molecular markers and death from prostate cancer. Ann Intern Med, 150, 595-603.
  13. Daniyal M, Siddiqui ZA, Akram M, et al (2014). Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pac J Cancer Prev, 15, 9575-8.
  14. Esfahani M, Ataei N, Panjehpour M (2015). Biomarkers for Evaluation of Prostate Cancer Prognosis. Asian Pac J Cancer Prev, 16, 2601-11.
  15. Fonseca GN, Srougi M, Leite KR, et al (2004). The role of HER2/neu, BCL2, p53 genes and proliferating cell nuclear protein as molecular prognostic parameters in localized prostate carcinoma. Sao Paulo Med J, 122, 124-7.
  16. Freedland SJ, deGregorio F, Sacoolidge JC, et al (2003). Preoperative p27 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J Urol, 169, 1325-30.
  17. Globocan (2012). Assessed the 23rd April 2016,
  18. Goto T, Nguyen BP, Nakano M, et al (2008). Utility of Bcl-2, P53, Ki-67, and caveolin-1 immunostaining in the prediction of biochemical failure after radical prostatectomy in a Japanese population. Urol, 72, 167-71.
  19. Ho CC, Seong PK, Zainuddin ZM, et al (2013). Retrospective study of predictors of bone metastasis in prostate cancer cases. Asian Pac J Cancer Prev, 14, 3289-92.
  20. Hughes C, Murphy A, Martin C, et al (2005). Molecular pathology of prostate cancer. J Clin Pathol, 58, 673-84.
  21. Inoue T, Segawa T, Shiraishi T, et al (2005). Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. Urol, 66, 332-7.
  22. Isharwal S, Miller MC, Epstein JI, et al (2008). Prognostic value of Her-2/neu and DNA index for progression, metastasis and prostate cancer-specific death in men with long-term follow-up after radical prostatectomy. Int J Cancer, 123, 2636-43.
  23. Kluth M, Harasimowicz S, Burkhardt L, et al (2014). Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. Int J Cancer, 135, 1369-80.
  24. Kuczyk MA, Serth J, Bokemeyer C, et al (1998). The prognostic value of p53 for long-term and recurrence-free survival following radical prostatectomy. Eur J Cancer, 34, 679-86.
  25. Larkin SE, Holmes S, Cree IA, et al (2012). Identification of markers of prostate cancer progression using candidate gene expression. Br J Cancer, 106, 157-65.
  26. Lazari P, Poulias H, Gakiopoulou H, et al (2013). Differential immunohistochemical expression of CD44s, E-cadherin and ${\beta}$-catenin among hyperplastic and neoplastic lesions of the prostate gland. Urol Int, 90, 109-16.
  27. Missaoui N, Trabelsi A, Parkin DM, et al (2010). Trends in the incidence of cancer in the Sousse region, Tunisia, 1993-2006. Int J Cancer, 127, 2669-77.
  28. Maru N, Ohori M, Kattan MW, et al (2001). Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum Pathol, 32, 828-33.
  29. Molinie V, Beuzeboc P, Mahjoub WK et al (2008). Molecular biology and prostate cancer: evolution or revolution? Ann Pathol, 28, 354-62.
  30. Molinie V (2008). Gleason's score: update in 2008. Ann Pathol, 28, 350-53.
  31. Quinn DI, Henshall SM, Sutherland RL (2005). Molecular markers of prostate cancer outcome. Eur J Cancer, 41, 858-87.
  32. Ramirez ML, Nelson EC, Evans CP (2008). Beyond prostate-specific antigen: alternate serum markers. Prostate Cancer, 11, 216-29.
  33. Ribal MJ, Fernandez PL, Lopez-Guillermo A, et al (2003). Low p27 expression predicts biochemical relapse after radical prostatectomy in patients with clinically localised prostate cancer. Anticancer Res, 23, 5101-6.
  34. Salomon L, Azria D, Bastide C, et al (2010). Recommendations Onco-Urology 2010: Prostate cancer. Prog Urol, 20, 217-51.
  35. Sirma H, Broemel M, Stumm L, et al (2013). Loss of CDKN1B/p27Kip1 expression is associated with ERG fusion-negative prostate cancer, but is unrelated to patient prognosis. Oncol Lett, 6, 1245-52.
  36. Rubio J, Ramos D, Lopez-Guerrero JA, et al (2005). Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol, 48, 745-51.
  37. Umbas R, Isaacs WB, Bringuier PP, et al (1994). Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res, 54, 3929-33.
  38. Van Dong H, Lee AH, Nga NH, et al (2014). Epidemiology and prevention of prostate cancer in Vietnam. Asian Pac J Cancer Prev, 15, 9747-51.
  39. Verhoven B, Yan Y, Ritter M, et al (2013). Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG). 94-08. Int J Radiat Oncol Biol Phys, 86, 317-23.
  40. Wang K, Peng HL, Li LK (2012). Prognostic value of vascular endothelial growth factor expression in patients with prostate cancer: a systematic review with meta-analysis. Asian Pac J Cancer Prev, 13, 5665-9.
  41. Wolff AC, Hammond ME, Hicks DG, et al (2013). Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol, 31, 3997-4013.
  42. Yamashita K, Denno K, Ueda T, et al (1993). Prognostic significance of bone metastases in patients with metastatic prostate cancer. Cancer, 71, 1297-302.<1297::AID-CNCR2820710421>3.0.CO;2-S
  43. Yang RM, Naitoh J, Murphy M, et al (1998). Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol, 159, 941-5.
  44. Zahir ST, Tafti HF, Rahmani K (2014). Overexpression of HER-2/neu in patients with prostatic adenocarcinoma. Asian Pac J Cancer Prev, 15, 6425-8.
  45. Zhang YF, Guan YB, Yang B, et al (2011). Prognostic value of Her-2/neu and clinicopathologic factors for evaluating progression and disease-specific death in Chinese men with prostate cancer. Chin Med J (Engl), 124, 4345-9.
  46. Zhigang Z, Wenlv S (2004). Prostate stem cell antigen (PSCA). expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer. World J Surg Oncol, 2, 13.