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P27kip1 and Ki-67 (MIB1) Immunohistochemical Expression in Radical Prostatectomy Specimens of Patients with Clinically Localized Prostate Cancer

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P27kip1 and Ki-67 (MIB1) Immunohistochemical Expression in Radical Prostatectomy Specimens of Patients with Clinically Localized Prostate Cancer in vivo 19: 911-920 (2005) p27kip1 and Ki-67 (MIB1) Immunohistochemical Expression in Radical Prostatectomy Specimens of Patients with Clinically Localized Prostate Cancer KYRIAKOS REVELOS1,4,5, CONSTANTINA PETRAKI1, ALKIVIADIS GREGORAKIS2, ANDREAS SCORILAS3, PANAGIOTIS PAPANASTASIOU2, ROXANE TENTA5 and MICHAEL KOUTSILIERIS5 1Department of Pathology and 2Urology Clinic, "Evangelismos" General Hospital, Athens; 3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens; 4Department of Pathology and Biomedical Research, 251 Hellenic Air Force General Hospital, Athens; 5Department of Experimental Physiology, Medical School, University of Athens, Goudi-Athens, 115 27, Greece Abstract. The immunohistochemical expressions (IE) of p27kip1 Prostate cancer (PC) is the most frequently diagnosed and Ki-67 (MIB-1), both involved in cell cycle regulation and cell malignancy in elderly men (1, 2). The widespread proliferation, and their ability to predict biochemical failure, were introduction of serum prostate specific antigen (PSA) assessed in patients with clinically localized prostate cancer who measurements, as a pre-screening tool for the detection of had underdone radical prostatectomy of curative intent. In PC in healthy men, has significantly increased the number addition, p27kip1 and Ki-67 (MIB1) expressions were correlated of men diagnosed with clinically localized PC and the with several pre-operative and post-operative parameters, such as number of patients who undergo radical prostatectomy with Gleason score, extracapsular extension, seminal vesicle curative intent. Disappointingly, biochemical failure is as involvement, pelvic lymph nodes metastasis, positive surgical high as 30-50% in patients with clinically localized PC margins, coexistence of high-grade prostatic intraepithelial following radical surgery (3, 4). The Gleason score, tumour neoplasia, tumour size, prostate volume and PSA levels. Our stage and pre-operative PSA levels are predictors, to a analysis involved 130 consecutive radical prostatectomy specimens. certain degree, of the biochemical failure. Ideally, clinical A statistically significant correlation of low p27kip1 IE with seminal decisions should be based on reliable tools capable of vesicles involvement, increased tumour volume and high pre- assessing the exact stage and aggressiveness of the disease operative PSA values was documented. Low p27kip1 IE was before surgery. Therefore, intensive clinical investigation significantly correlated with an increased likelihood of biochemical aims at the development of reliable molecular techniques failure after radical prostatectomy. In addition, the increased IE of for the detection of the transcripts of PSA and prostate Ki-67 (MIB1) correlated significantly with metastatic disease in the specific membrane antigen (PSMA) in the peripheral blood pelvic lymph nodes and was a significant predictor of biochemical and in the bone marrow biopsy specimens of patients with failure. Cox regression analysis, which included p27kip1 expression, clinically localized PC, with sometimes promising, albeit not Ki-67 (MIB1) expression and all the pre-operative and post- always reproducible, data (5-8). Indeed, PC, which is operative parameters, showed that pelvic lymph node involvement already metastatic at diagnosis or able to produce metastasis and Ki-67 (MIB1) IE were independent prognostic markers of as a result of its histological grade, must be distinguished biochemical failure after radical prostatectomy. from indolent prostate cancer tumours. Patients with aggressive tumours should be candidates for adjuvant therapy before or after surgery and radiotherapy. For this reason, in prostate cancer (PC) there is an urgent need to Correspondence to: Dr. Michael Koutsilieris, MD, Ph.D., Professor develop reliable molecular methods and new prognostic & Director, Department of Experimental Physiology, Medical markers capable of predicting disease spread at diagnosis School, University of Athens, Goudi-Athens 115 27, Greece. Tel: and disease recurrence after surgery of curative intent. (30210)-7462597, Fax: (30210)-7462571, e-mail: mkouts@ In this study, the prognostic value of tissue markers, such medscape.com as p27kip1 and Ki-67 (MIB-1), both involved in cell cycle Key Words: Prostate cancer, radical prostatectomy, p27kip1, Ki-67 regulation and cell proliferation vis-à-vis biochemical failure (MIB1), biochemical failure. after radical prostatectomy, were addressed. In a variety of 0258-851X/2005 $2.00+.40 911 in vivo 19: 911-920 (2005) human tumours p27kip1 expression is decreased, and low specimen margin, extracapsular extension into periprostatic tissue, p27kip1 expression has been associated with poor outcome seminal vesicle and pelvic lymph nodes involvement, prostate in breast, colorectal and lung carcinomas (9-12). In PC weight, tumour volume and coexistence of high-grade PIN. specimens, suppressed p27kip1 expression is also correlated The immunohistochemical streptavidin biotin peroxidase protocol using the DAKO LSAB+Kit Peroxidase was performed, with with advanced pathological features, tumour progression commercially available antibodies: the mouse monoclonal antibody and poor survival (13-18). In addition, some previous against p27kip1 (clone SX53G8; DAKO, Glostrup, Denmark), at a studies showed that the proliferation fraction of primary PC, dilution of 1:10 and the mouse monoclonal antibody against Ki-67 as assessed by Ki-67 (MIB1) expression, was associated with (clone MIB-1; DAKO), at a dilution of 1:10. Staining procedures grade or stage of PC and clinical outcome of patients after included deparaffinization in warm xylene for 5 min with two radical prostatectomy (18-26). changes of xylene at room temperature, followed by rehydration by Therefore, the immunohistochemical expression (IE) of transfer through graded alcohols. Endogenous peroxidase activity was blocked with 0.5% H 0 in methanol for 10 min. The sections p27kip1 and Ki-67 (MIB1) was assessed in radical 2 2 were pre-treated with 10 mmol/L citrate buffer (pH 6.1) in a prostatectomy specimens of patients with PC. In addition, microwave for 5 min and incubated overnight at 4ÆC with the hK10 multivariate analysis was performed on the IE of these two primary rabbit polyclonal and mouse monoclonal antibodies in 3% cell cycle and proliferation regulators and of several BSA. After two washes of the sections in 50 mM Tris buffer (pH clinicopathological parameters, such as Gleason score, 7.6), the biotinylated Link (DAKO Corporation, USA) was applied extracapsular extension, seminal vesicle involvement, pelvic for 15 min and a streptavidin-peroxidase conjugate followed for lymph nodes metastasis, positive surgical margins, another 15 min. The enzymatic reaction was developed in a freshly coexistence of high-grade prostatic intraepithelial neoplasia prepared solution of 3,3’-diaminobenzidine tetrahydrochloride using DAKO Liquid DAB Substrate-Chromogen Solution for 10 min (PIN), tumour size, prostate volume and pre-operative PSA (brown colour). The sections were then counterstained with levels versus biochemical failure after radical prostatectomy. haemalum, dehydrated, cleared in xylene and mounted. Most of the detectable staining was heterogeneous and focal in Materials and Methods nature. For p27kip1 scoring, an area with the lowest density of positive cells for the protein expression was chosen. In contrast to In this study, 130 consecutive radical prostatectomy specimens, Ki-67 scoring, the area with maximum immunostaining was from patients who underwent radical prostatectomy for localized selected. Then malignant cells were counted at 400x magnification. PC at the "Evangelismos" General Hospital, Athens, Greece, The number of cells with positive nuclear staining for p27kip1 and between 01/1994 and 12/2001, were evaluated. The median age of Ki-67 (MIB-1) were recorded. Then the results were grouped and the patients was 66 years (range 47-76 years). Pre-operative PSA divided into low and high expression groups. p27kip1 revealed a median PSA of 9.23 (2.5-45.0) ng/ml. Follow-up was immunoexpression in neoplastic cells was scored as high if more available for 94 patients, so the other 36 (referred for surgery to than 30% of the cells were stained and as low if less than 30% of our hospital from rural areas of Greece and followed-up locally) the cells were positive (31, 32). For the proliferation index Ki-67 were excluded from the statistical analysis, which concerned (MIB-1), a cut-off point of 5% was used to distinguish high and biochemical failure. The follow-up period ranged from 1 to 97 low expression groups. months (median: 28 months). A cut-off of 0.2 ng/ml serum PSA, Patients were subdivided into groups based on different clinical or on at least two occasions, with the second elevation measured at pathological parameters. In this analysis, p27kip1 and Ki-67 (MIB-1) least 6 months after the first, established a biochemical failure. were classified into two categories (positive and negative groups), and Radical prostatectomy specimens were submitted fresh for associations between gene expression status and other qualitative routine pathological examination. The specimens were weighed, variables were analyzed using the Fisher’s Exact test. Because the inked and fixed in buffer-formalin. Routine processing included distribution of serum PSA, tumor percentage, prostate weight and sectioning and paraffin- embedding of the whole prostate gland. patients’ age were not
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