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Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability

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Abstract

Introduction

This study aims to clarify whether neuroendocrine differentiation (NED) and/or proliferation activity assessed by means of Ki67 staining index (Ki67SI) might aggravate other established adverse prognostic parameters commonly used for predicting outcome in surgically treated prostate cancer, and to assess inter-observer variability in assigning NED and Ki67 SI.

Material and methods

A total of 528 patients surgically treated due to prostate cancer were evaluated in this study. Relevant data were retrospectively obtained by chart review. Immunostaining with antibodies directed against Chromogranin A and Ki67 was performed on archived surgical material, and was evaluated by two independent histopathologists blinded to the specimens. Surveying a median postsurgical follow-up of 46.4 months, postsurgical serum PSA-levels were regularly documented for identifying biochemical progress. Multivariate analysis was performed by means of the Cox regression hazards regression method to evaluate possible aggravations of established adverse prognostic parameters (nodal status, tumour stage, pretherapeutic PSA-level, and Gleason score) by NED and/or Ki67SI. Ki67 SI and NED were shown to significantly aggravate these established adverse prognostic parameters, and were found to be characterized by negligible inter-observer variability.

Conclusion

Ki67 SI and NED should be advocated to be rendered by the histopathologist because both parameters can be immunohistochemically determined without much additional expense in time and cost involved. This concept is rewarded by an additional gain of prognostic accuracy in evaluating individual risk profile after surgery.

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References

  1. Green GA, Hanlon AL, Al-Saleem T, Hanks GE (1998) A Gleason score of 7 predicts a worse outcome for prostate carcinoma patients treated with radiotherapy. Cancer 83:971–976

    Article  PubMed  CAS  Google Scholar 

  2. Yokomizo A, Murai M, Baba S, Ogawa O, Tsukamoto T, Niwakawa M, Tobisu K, Kinukawa N, Naito S (2006) Percentage of positive biopsy cores, properative prostate specific antigen (PSA) level, pT and Gleason score as predictors of PSA recurence afte radical prostatectomy: a multi-institutional outcome study in Japan. BJU Int 98:549–553

    Article  PubMed  CAS  Google Scholar 

  3. Sakr WA, Tefilli MV, Grignon DJ, Banerjee M, Dey J, Gheiler EL, Tiguert R, Powell IJ, Wood DP (2000) Gleason score 7 prostate cancer: a heterogeneous entity? Correlation with pathologic parameters and disease-free survival. Urology 56:730–734

    Article  PubMed  CAS  Google Scholar 

  4. Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC (2003) Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 169:517–523

    Article  PubMed  Google Scholar 

  5. Epstein JI, Amin M, Bocco– Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R (2005) Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 216:34–63

    Article  PubMed  Google Scholar 

  6. Freedland SJ, Aronson W, Presti JC, Kane CJ, Terris MK, Elashoff D, Amling CL, The SEARCH Database Study Group (2003) Should a positive margin following radical prostatectomy be pathological stage T2 or T3? Results from the SEARCH database. J Urol 169:2142–2146

    Article  PubMed  Google Scholar 

  7. Manoharan M, Bird VG, Kim SS, Civantos F, Soloway MS (2003) Outcome after radical prostatectomy with a pretreatment prostate biopsy Gleason score of ≥8. BJU Int 92:539–544

    Article  PubMed  CAS  Google Scholar 

  8. May M, Kaufmann O, Hammermann F, Loy V, Siegsmund M (2007) Prognostic impact of lymphovascular invasion in radical prostatectomy specimens. BJU Int 99:539–544

    Article  PubMed  Google Scholar 

  9. Li R, Heydon K, Hammond ME, Grignon DJ, Roach M, Wolkov HB, Sandler HM, Shipley WU, Pollack A (2004) Ki-67 staining index predicts distant metastasis and survival in locally advanced prostate cancer treated with radiotherapy: an analysis of patients in radiation theapy oncology group protocol 86–10. Clin Cancer Res 15:4118–41224

    Article  Google Scholar 

  10. Pollack A, DeSilvio M, Khor LY, Li R, Al-Saleem TI, Hammond ME, Venkatesan V, Lawton CA, Roach M 3rd, Shipley WU, Hanks GE, Sandler HM (2004) Ki-67 staining index is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 1992–2002. J Clin Oncol 22:2133–2140

    Article  PubMed  CAS  Google Scholar 

  11. Inoue T, Segawa T, Shiraishi T, Yoshida T, Toda Y, Yamada T, Kinukawa N, Kinoshita H, Kamoto T, Ogawa O (2005) Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. Urology 66:332–337

    Article  PubMed  Google Scholar 

  12. Grobholz R, Griebe M, Sauer CG, Michel MS, Trojan L, Bleyl U (2005) Influence of neuroendocrine tumor cells on proliferation in prostatic carcinoma. Hum Pathol 36:562–570

    Article  PubMed  CAS  Google Scholar 

  13. Tamas EF, Epstein JI (2006) Prognostic significance of paneth cell–like neuroendocrine differentiation in adenocarcinoma of the prostate. Am J Surg Pathol 30:980–985

    Article  PubMed  Google Scholar 

  14. Nelson EC, Cambio AJ, Yang JC, Ok JH, Lara PN, Evans CP (2007) Clinical implications of neuroendocrine differentiation in prostate cancer. Prostate Cancer Prostatic Dis 10:6–14

    Article  PubMed  CAS  Google Scholar 

  15. Kinebuchi Y, Noguchi W, Irie K, Nakayama T, Kato H, Nishizawa O (2007) Relapsed prostate cancer with neuroendocrine differentiation and high serum levels of carcinoembryonic antigen without elevation of prostate-specific antigen: a case reprot. Int J Urol 14:147–149

    Article  PubMed  CAS  Google Scholar 

  16. Grimaldi F, Valotto C, Barbina G, Visentini D, Trianni A, Cerruto MA, Zattoni F (2006) The possible role of Chromogranin A as a prognostic factor in organ–confined prostate cancer. Int J Biol Markers 21:229–234

    PubMed  CAS  Google Scholar 

  17. May M, Siegsmund M, Hammermann F, Loy V, Gunia S (2007) Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy. Scand J Urol Nephrol 41:375–381

    Article  PubMed  CAS  Google Scholar 

  18. Di Sant`Agnese PA, de Mesy Jensen KL (1987) Neuroendocrine differentiation in prostatic carcinoma. Hum Pathol 18:849–856

    Article  CAS  Google Scholar 

  19. Honn KV, Aref A, Chen YQ, Cher ML, Crissman JD, Forman JD, Gao X, Grignon D, Hussain M, Porter AT, Pontes JE, Powell II, Redman B, Sakr W, Severson R, Tang DG, Wood DP Jr (1996) Prostate cancer-old problems and new approaches. (Part II. Diagnostic and prognostic markers, pathology and biological aspects). Pathol Oncol Res 2:191–211

    Article  PubMed  CAS  Google Scholar 

  20. Schiffer E (2004) Biomarkers in prostate cancer. World J Urol 25:557–562

    Article  CAS  Google Scholar 

  21. Aaltomaa S, Karja V, Lipponen P, Isotalo T, Kankkunen JP, Talja M, Mokka R (2006) Expression of Ki-67, cyclin D1 and apoptosis markers correlated with survival in prostate cancer patients treated by radical prostatectomy. Anticancer Res 26:4873–4878

    PubMed  CAS  Google Scholar 

  22. Ojea Calvo A, Mosteiro Cervino MJ, Dominguez Freire F, Alonso Rodigro A, Rodriguez Iglesias B, Benavente Delgado J, Barros Rodriguez JM, Gonzalez Pineiro A (2004) The usefulness of Ki67 expression in the biopsy specimens, to predict the biochemical progression of the prostate cancer after radical prostatectomy. Actas Urol Esp 28:650–660

    PubMed  CAS  Google Scholar 

  23. Hoosein NM (1998) Neuroendocrine and immune mediators in prostate cancer progression. Front Biosci 15:1274–1279

    Google Scholar 

  24. Diaz M, Abdul M, Hoosein N (1998) Modulation of neuroendocrine differentiation in prostate cancer by interleukin-1 and -2. Prostate Suppl 8:32–36

    Article  PubMed  CAS  Google Scholar 

  25. Chiao JW, Hsieh TC, Xu W, Sklarew RJ, Kancherla R (1999) Development of human prostate cancer cells to neuroendocrine-like cells by interleukin-1. Int J Oncol 15:1033–1037

    PubMed  CAS  Google Scholar 

  26. Sumitomo M, Shen R, Walburg M, Dai J, Geng Y, Navarro D, Boileau G, Papandreou CN, Giancotti FG, Knudsen B, Nanus DM (2000) Neutral endo-peptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling. J Clin Invest 106:1399–1407

    Article  PubMed  CAS  Google Scholar 

  27. lbrecht M, Doroszewicz J, Gillen S, Gomes I, Wilhelm B, Stief T, Aumüller G (2004) Proliferation of prostate cancer cells and activity of neutral endopeptidase is regulated by bombesin and IL-1 beta with IL-1 beta acting as a modulator of cellular differentiation. Prostate 58:82–94

    Article  CAS  Google Scholar 

  28. Paule B, Terry S, Kheuang L, Soyeux P, Vacherot F, de la Taille A (2007) The NF-kappaB/IL-6 pathway in metastatic androgen-independent prostate cancer: new therapeutic approaches? World J Urol 25:477–489

    Article  PubMed  CAS  Google Scholar 

  29. Potter SR, Epstein JI, Partin AW (2000) Seminal vesicle invasion by prostate cancer: prognostic significance and therapeutic implications. Rev Urol 2:190–195 Summer

    PubMed  CAS  Google Scholar 

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Correspondence to Sven Gunia.

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Gunia, S., Albrecht, K., Koch, S. et al. Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability. World J Urol 26, 243–250 (2008). https://doi.org/10.1007/s00345-008-0257-0

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  • DOI: https://doi.org/10.1007/s00345-008-0257-0

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