前列腺癌组织中蛋白表达与内分泌治疗后进展的相关性研究

目的 探讨前列腺癌内分泌治疗前癌组织中多种蛋白标记表达与内分泌治疗后发生进展的相关性,筛选内分泌治疗后进展的预测因子.方法 收集116例接受内分泌治疗的前列腺癌患者的临床病理资料,检测患者内分泌治疗前癌组织中雄激素受体(AR)、上皮型钙黏附索(E-cad-herin)、嗜铬粒蛋白A(CgA)、核增殖抗原(Ki67)、凋亡抑制蛋白(Survivin)、EZH2、hepsin蛋白表达,应用Cox比例风险模型进行多因素分析.结果 Ki67、EZH2、Survivin 3种蛋白表达与传统临床病理学因素存在Spearman等级相关.单因素分析中发现临床分期(P<0.001)、Gleason评分(P=0.005)、治疗前血清PSA值(P<0.001)以及Ki67(P=0.032)、Survivin蛋白(P=0.002)表达与内分泌治疗后的进展相关,多因素分析结果 显示临床分期(T_x N_+/M_+)(P<0.001)、高病理分级(Gleason评分≥8分)(P-0.038)和Survivin蛋白高表达(p＝0.031)是内分泌治疗后进展的重要危险因素.其中T_x N_+/M_+者67例(57.8%),Gleason评分≥8分者56例(48.3%),Survivin蛋白高表达者91例(78.4%). 结论 临床分期、病理分级、Survivin蛋白表达对于预测前列腺癌内分泌治疗后进展有重要意义.     

A comparison of the biological features between prostate cancers arising in the transition and peripheral zones

OBJECTIVES: To investigate differences in the biological features of prostate cancer according to the zonal origin. PATIENTS AND METHODS: Among 172 consecutive patients who had a radical prostatectomy (RP), the study included 124 diagnosed as having either transition zone (TZ) or peripheral zone (PZ) cancer, defined according to whether there was > 70% of the cancer area in the TZ or PZ, respectively. The clinicopathological features were then compared between these groups. In addition, the RP specimens were stained immunohistochemically with antibodies to Ki-67, Bcl-2, matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF). RESULTS: Twenty-four patients were diagnosed as having TZ cancer and the remaining 100 as having PZ cancer. Prostate specific antigen (PSA) values in patients with TZ cancer were significantly higher than in those with PZ cancer. Tumour volume in TZ cancer was significantly greater than that in PZ cancer, but there was no significant difference in biochemical recurrence-free survival between the groups. Immunohistochemistry showed that despite there being no differences in Bcl-2 and VEGF expression between TZ and PZ cancers, there was significantly greater expression of Ki-67, MMP-2 and MMP-9 in PZ than TZ cancers. CONCLUSIONS: Despite there being no significant difference in biochemical recurrence-free survival after RP between patients with TZ and PZ cancers, there was less cell proliferation and biomarker levels related to invasive potential in TZ than in PZ cancers.     

Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer： the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors

A cure cannot be assured for all men with clinically localized prostate cancer undergoing radical treatment. Molecular markers would be invaluable if they could improve the prediction of occult metastatic disease. This study was carried out to investigate the expression of BCL-2, Ki-67, p53 and E-cadherin in radical prostatectomy specimens. We sought to assess their ability to predict early biochemical relapse in a specific therapeutic setting. Eighty-two patients comprising 41 case pairs were matched for pathological stage, Gleason grade and preoperative prostate-specific antigen （PSA） concentration. One patient in each pair had biochemical recurrence （defined as PSA ≥ 0.2 ng mL^-1 within 2 years of surgery） and the other remained biochemically free of disease （defined as undetectable PSA at least 3 years after surgery）. Immunohistochemical analysis was performed to assess marker expression on four replicate tissue microarrays constructed with benign and malignant tissue from each radical prostatectomy specimen. Ki-67, p53 and BCL-2, but not E-cadherin, were significantly upregulated in prostate adenocarcinoma compared with benign prostate tissue （P 〈 0.01）. However, no significant differences in expression of any of the markers were observed when comparing patients who developed early biochemical relapse with patients who had no biochemical recurrence. This study showed that expression of p53, BCL-2 and Ki-67 was upregulated in clinically localized prostate cancer compared with benign prostate tissue, with no alteration in E-cadherin expression. Biomarker upregulation had no prognostic value for biochemical recurrence after radical prostatectomy, even after considering pathological stage, whole tumour Gleason grade and preoperative serum PSA level.     

Persistent expression of Aurora-A after neoadjuvant hormonal therapy as a predictor of a poor clinical outcome in patients undergoing radical prostatectomy for prostate cancer

OBJECTIVES: To characterize the changes in the expression of Aurora-A protein in prostate cancer before and after androgen-withdrawal therapy, and to assess the prognostic significance of the Aurora-A expression in patients undergoing radical prostatectomy (RP) after neoadjuvant hormonal therapy (NHT). PATIENTS AND METHODS: The study included 97 patients with clinically localized prostate cancer who received NHT followed by RP. Paired needle biopsy and corresponding RP specimens obtained from these patients were analysed for the expression of Aurora-A protein by immunohistochemical staining. These findings were then evaluated in relation to several clinicopathological factors. RESULTS: There were various levels of Aurora-A protein expression in most prostate cancer tissues before NHT; however, the Aurora-A expression in RP specimens after NHT was significantly down-regulated compared with that in corresponding needle-biopsy specimens. The expression level of Aurora-A in biopsy specimens was significantly associated with the biopsy Gleason score, but not with other factors available before RP. The Aurora-A expression in the RP specimens correlated significantly with the preoperative value of the serum prostate specific antigen and pathological stage, but not with any other clinicopathological factors examined. Furthermore, cell proliferative activity in the RP specimens, measured by Ki-67 immunostaining, was proportional to the expression of Aurora-A. The biochemical recurrence-free survival in patients with a persistent Aurora-A expression in RP specimens was significantly lower than that in those with a weak Aurora-A expression, but the expression level of Aurora-A was not an independent predictor of biochemical recurrence. CONCLUSIONS: Despite the lack of any independent significance, the expression level of Aurora-A in prostate cancer tissue after NHT, which might inversely reflect the therapeutic effect of NHT, could therefore be a useful variable for predicting biochemical recurrence in patients undergoing RP.     

High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy

BACKGROUND: Prostate cancer (PCa) is androgen dependent and is regulated by androgen/androgen receptor (AR) signaling pathway. However, the clinical significance of AR is in question. In this regard, we have correlated levels of AR expression with some well-established clinical and pathologic parameters and assessed the prognostic value of AR expression in PCa patients treated with radical prostatectomy. DESIGN: A total of 640 cases treated with radical prostatectomy were used to build tissue microarrays. Normal prostate tissue, benign prostatic hyperplasia, and index tumor were cored in triplicate (0.6 mm). An array (2 mm) of 177 metastatic PCa was built as well. Slides were immunostained with an antibody to AR and Ki-67 and digitized. Correlations between AR expression and clinicopathologic variables were analyzed by the Spearman test. Biochemical recurrence-free survival analysis was performed using Kaplan-Meier analysis, and Cox proportional hazard regression was used to determine the probability of disease recurrence. RESULTS: AR was found in epithelial nuclei of both benign and cancer tissues. AR index was higher in normal prostate tissues than that in PCa and benign prostatic hyperplasia and decreased in metastases than PCa. High level of AR expression was correlated with clinical stage, lymph node status, extracapsular extension, seminal vesicle invasion, and Gleason score. High levels of AR status also correlated with high Ki-67 index (r = 0.211, P = 0.0000). By Kaplan-Meier actuarial model, high expression of AR was predictive of a higher probability of recurrence (P = 0.0046, hazards ratio 2.72 [confidence interval 1.28-4.011]). By multivariate analysis, a high level of AR expression was an independent prognostic indicator of biochemical recurrence-free survival (P = 0.0042; hazards ratio 2.422 [confidence interval 1.32-4.44]). CONCLUSIONS: High levels of AR are associated with increased proliferation, markers of aggressive disease and are predictive of decreased biochemical recurrence-free survival independently. This confirms the role of AR in tumor growth and progression in hormonally naive PCa.     

Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens

PURPOSES: To elucidate the prognostic value of the immunohistochemical (IHC) expression of Bcl-2, Bax, Cox-2 and Ki-67 antigen in biopsy cores (C) and surgical specimens (SP) of prostate cancer (PC) and to determine the C to SP reproducibility. MATERIAL AND METHODS: The IHC study was carried out in 91 patients operated by means of radical prostatectomy (RP) with available formalin-fixed paraffin-embedded material from both C and SP. RESULTS: The IHC expression of Bcl-2 in C and SP was very low (5%). Bax was expressed in almost all the patients and did not show any prognostic value. We observed a good reproducibility between C and SP for all molecules except with Bax. In prostate C, Ki-67 and Cox-2 were considered positive in 42.9% and 67% of the patients respectively, and were related to disease-free survival in the univariate analysis. The expression of these two markers in SP was observed in 51.6% and 79.1% of the patients and the expression of Ki-67 in SP maintained its independence as prognostic factor in the multivariate analysis related to disease-free survival. CONCLUSIONS: The IHC expression of Ki-67 and Cox-2 proteins in our study do offer valuable prognostic information, mostly the first one. Thus, we think these markers might be studied in larger series of patients for its further validation as prognostic factors in prostate biopsies.     

Expression of major heat shock proteins in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy

PURPOSE: We evaluated expression levels of major heat shock proteins in radical prostatectomy specimens to clarify the significance of heat shock protein expression in prostate cancer. MATERIALS AND METHODS: Expression levels of heat shock proteins 27, 70 and 90 in radical prostatectomy specimens from 172 patients with clinically organ confined prostate cancer who had not received neoadjuvant hormonal therapy were measured by immunohistochemical staining. Cell proliferative activities and apoptotic features in these specimens were investigated using Ki-67 immunostaining and TUNEL assay, respectively. These findings were analyzed with respect to several clinicopathological factors. RESULTS: Various levels of heat shock protein 27 expression were noted in all prostate cancer specimens. Expression levels of heat shock protein 27 in prostate cancer tissues was significantly associated with pathological stage, Gleason score, surgical margin status, lymph node metastasis and tumor volume but not with other parameters, including patient age, serum prostate specific antigen and perineural invasion. Similarly most prostate cancer tissues showed heat shock protein 70 and 90 expression. However, there was no significant correlation between expression levels of these 2 heat shock proteins and several clinicopathological factors examined. Cell proliferative activity in prostate cancer specimens was significantly associated with heat shock protein 27 expression but not with that of heat shock proteins 70 and 90, while there was no significant correlation between the apoptotic index and the expression of these 3 heat shock proteins. Furthermore, despite the lack of prognostic significance in heat shock proteins 70 and 90 expression, biochemical recurrence-free survival in patients with strong heat shock protein 27 expression in radical prostatectomy specimens was significantly lower than that in those with weak heat shock protein 27 expression. However, multivariate analysis showed that strong heat shock protein 27 expression could not be an independent predictor of biochemical recurrence after radical prostatectomy. CONCLUSIONS: These findings suggest that, despite the limited significance of heat shock proteins 70 and 90 expression, heat shock protein 27 may be involved in the progression of prostate cancer. The expression level of heat shock protein 27 in prostate cancer tissue could be used as a useful predictor of biochemical recurrence in patients undergoing radical prostatectomy.     

Expression of potential molecular markers in renal cell carcinoma: impact on clinicopathological outcomes in patients undergoing radical nephrectomy

OBJECTIVES

To evaluate the expression levels of several potential molecular markers in renal cell carcinoma (RCC), to clarify the significance of these markers as prognostic predictors in patients undergoing radical nephrectomy (RN).

PATIENTS AND METHODS

The study included 153 patients with clinically organ‐confined RCC undergoing RN. Expression levels of 12 proteins, including Aurora‐A, Bcl‐2, Bcl‐xL, clusterin, heat‐shock protein 27 (HSP27), HSP70, HSP90, Ki‐67, matrix metalloproteinase (MMP)‐2 and ‐9, p53 and vascular endothelial growth factor, in RN specimens obtained from these 153 patients were measured by immunohistochemical staining.

RESULTS

Of the 12 markers, clusterin, HSP27, Ki‐67, MMP‐2 and ‐9 expression were significantly associated with several conventional prognostic factors. Univariate analysis also identified these five markers as significant predictors of disease recurrence, while mode of presentation, pathological stage, grade and microvascular invasion were also significant. Of these significant factors, Ki‐67 expression, pathological stage and microvascular invasion appeared to be independently related to disease recurrence. Furthermore, there were significant differences in recurrence‐free survival according to positive numbers of these three independent factors, i.e. disease recurred in four of 56 patients who were negative for risk factors (7%), 17 of 71 positive for one risk factor (24%), and 20 of 26 positive for two or three risk factors (77%).

CONCLUSIONS

Combined evaluation of Ki‐67 expression, pathological stage and microvascular invasion would be particularly useful for further refinement of the system for predicting the outcome after RN for patients with RCC.     

Prognostic value of cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer

PURPOSE: Molecular tissue markers may give the clinician additional information about patients with prostate cancer at risk for treatment failure after retropubic radical prostatectomy. We substantiate the prognostic value of 3 tissue markers, the cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s, in addition to more conventional pathological prognosticators in an historical (before prostate specific antigen) cohort of patients with prostate cancer. MATERIALS AND METHODS: Representative tumor sections from 92 patients who underwent retropubic radical prostatectomy were immunohistochemically stained with antibodies against p27(kip1), MIB-1 (Ki-67) and CD44s, and assessed in a semiquantitative manner. Gleason score and pathological tumor stage were recorded. All variables were correlated with clinical progression and disease specific survival on univariate and multivariate analyses. RESULTS: On univariate analysis low (less than 50%) p27(kip1), high (10% or greater) MIB-1 and loss of CD44s expression were significantly associated with clinical outcome parameters, although MIB-1 did not reach statistical significance for disease specific survival. All 3 molecules were highly correlated with Gleason score and pathological tumor stage. Multivariate analysis showed that low p27kip1 was independent of grade and stage in predicting clinical recurrence (p <0.001) and disease specific survival (p = 0.045), while loss of CD44s was an additional independent prognostic factor for clinical recurrence (p = 0.02). CONCLUSIONS: Reduced p27(kip1) expression is an independent predictor of poor outcome in prostate cancer, while MIB-1 is not. Decreased expression of CD44s yields additional information in predicting clinical recurrence. These tissue markers may identify patients at risk for disease recurrence after retropubic radical prostatectomy who may benefit from adjuvant therapy.     

Expression of urokinase-type plasminogen activator system in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy

The objective of this study was to evaluate the expression levels of urokinase-type plasminogen activator (uPA) system in radical prostatectomy (RP) specimens in order to clarify the significance of the uPA system in prostate cancer. Expression levels of uPA, uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and PAI-2 in RP specimens obtained from 153 patients with clinically organ-confined prostate cancer who had not received any neoadjuvant therapies were evaluated by immunohistochemical staining. Various expression levels of uPA, uPAR, PAI-1, and PAI-2 were noted in the majority of prostate cancer specimens. Expression levels of uPA and uPAR were significantly associated with major prognostic indicators, including pathological stage, Gleason score, lymphatic invasion, surgical margin status and lymph node metastasis. However, PAI-1 expression was related to only pathological stage and surgical margin status, and there was no significant association between the expression level of PAI-2 and several parameters examined. Despite the lack of prognostic significance in PAI-2 expression, biochemical recurrence-free survival of patients with strong uPA, uPAR, and PAI-1 expression was significantly lower than that of those with weak uPA, uPAR, and PAI-1 expression, respectively. Furthermore, strong expression of uPA in addition to a Gleason score, positive surgical margin, and lymph node metastasis could be independent predictors for biochemical recurrence after RP. These findings suggest that the uPA system may be involved in the progression of prostate cancer, and that the expression level of uPA in prostate cancer tissue could be used as a useful predictor of biochemical recurrence in patients undergoing RP.     

Expression profile of CD44s,CD44v6, and CD44v10 in localized prostate cancer: Effect on prognostic outcomes following radical prostatectomy

ObjectivesTo investigate the expression of CD44 standard form (CD44s) and 2 major variant exons (CD44v6 and CD44v10) in localized prostate cancer (PC) to determine the prognostic significance of these markers following radical prostatectomy (RP).Materials and methodsExpression levels of CD44s, CD44v6, and CD44v10 in RP specimens from 160 consecutive patients with clinically localized PC were evaluated by immunohistochemical staining.ResultsOf these 3 markers, expression level of CD44v6 was closely associated with several conventional prognostic factors. Univariate analysis identified CD44v6 expression in addition to serum prostate-specific antigen level, Gleason score, seminal vesicle invasion, and surgical margin status as significant predictors for biochemical recurrence (BR). Of these significant factors, CD44v6 expression, serum prostate-specific antigen level, and surgical margin status appeared to be independently associated with BR on multivariate analysis. We observed significant differences in BR-free survival according to the positive numbers of these 3 independent factors; i.e., BR occurred in 0 (0%) of 42 patients who had negative results for risk factors, 9 (16.7%) of 54 who had positive results for 1 risk factor, and 31 (48.4%) of 64 who had positive results for 2 or 3 risk factors.ConclusionsAssessment of the expression levels of CD44v6 in RP specimens in addition to conventional prognostic parameters would contribute to the accurate prediction of the biochemical outcome in patients with localized PC who underwent RP.     

Immunohistochemical BCL-2 and Ki-67 expression predict survival in prostate cancer patients followed expectantly

The prognostic value of BCL-2 expression, solely and combined with Ki-67 expression, was determined in prostate cancer patients followed expectantly. Furthermore, associations with well established prognostic markers were tested. Formalin fixed, paraffin-embedded tumour tissue obtained at diagnosis was immunohistochemically investigated in 221 patients with a 15 y median follow-up time. BCL-2 protein was expressed in 114 (52%) tumours and was significantly associated with tumour stage (P=0.01). The prognostic value of BCL-2 expression was significant, using both disease-specific (P=0.0015) and overall survival (P=0.005) as endpoint. Patients with a combined BCL-2 negative/Ki-67 'low' tumour had the most favourable prognosis. This combined BCL-2/Ki-67 variable was of independently prognostic value in both the entire population (P=0.0001) and in the clinically localized subpopulation (P=0.035).     

Detection of the 67-kD laminin receptor in prostate cancer biopsies as a predictor of recurrence after radical prostatectomy.

OBJECTIVES: Reliable prognostic indicators are needed for a better pretherapeutic assessment of the agressiveness of organ-confined prostate cancer (PC) lesions. The 67-kD laminin receptor (67LR) is a cell-surface-associated protein involved in the acquisition of the invasive and metastatic phenotype of a variety of human cancer cell types. We have previously shown that 67LR detection in PC tissues from radical prostatectomy (RP) specimens is an independent predictor of biochemical (PSA) relapse in patients with clinically localized PC. In this study, we assessed 67LR detection in diagnostic PC biopsies as a predictor of biochemical relapse after RP. METHODS: Diagnostic biopsy and subsequent RP tissue specimens from 151 patients with clinically localized PC were immunohistochemically analyzed for 67LR expression. The level of 67LR expression was evaluated by both intensity and extent of the staining. Clinicopathological preoperative and postoperative parameters, including 67LR expression, were correlated with each other and tested as predictors of biochemical relapse. RESULTS: 67LR was detected in 67.5 and 68.2% of biopsies and RPs, respectively. 67LR detection in RP specimens was an independent predictor of relapse. The level of 67LR expression in the biopsy was significantly associated with the biopsy Gleason score (p<0.05) but failed to predict the pathological stage (p>0.1). Biochemical progression-free estimates for patients whose biopsy did or did not express the protein differed with only borderline statistical significance (p = 0.05). Multivariate analysis identified biopsy Gleason score as the only independent preoperative predictor of recurrence. Significant discrepancies in levels of 67LR expression were found between matched biopsy and RP specimens (p<0.05), with exact agreement rates <40%. CONCLUSIONS: 67LR detection in PC biopsies was not a significant preoperative predictor of outcome after RP. Heterogeneity of 67LR expression and biopsy sampling errors most likely represented the main reasons for discordant results between biopsy and RP specimens.     

The expression of vascular endothelial growth factor is associated with the risk of cancer progression after radical prostatectomy

OBJECTIVE: To analyse the prognostic value of vascular endothelial growth factor (VEGF) in men with clinically localized prostate cancer. PATIENTS AND METHODS: Paraffin wax-embedded sections from the radical prostatectomy (RP) specimens of 40 men operated for clinically localized prostate cancer were used to build tissue microarrays. Of these patients, 17 had cancer progression and bone metastases after RP (group 1), and 23 remained free-of-tumour recurrence after RP (group 2). VEGF-A expression was examined in the RP specimens using immunohistochemistry. RESULTS: The groups had similar tumour characteristics in terms of prostate-specific antigen level, Gleason score, and pathological stage. VEGF-A expression was significantly higher in group 1 than in group 2 (P=0.046). In logistic regression analysis, VEGF-A expression was the most significant predictive factor of cancer progression after RP. CONCLUSION: VEGF-A expression in prostate cancer tissue is associated with the risk of cancer progression after RP. These results suggest that VEGF-A expression has a prognostic impact in clinically localized prostate cancer.     

The prognostic value of p53, Ki-67 and matrix metalloproteinases MMP-2 and MMP-9 in transitional cell carcinoma of the renal pelvis and ureter

AIM: To investigate the prognostic and predictive relevance of p53 protein, Ki-67 antigen, MMP-2 and MMP-9 in patients with transitional cell carcinoma (TCC) of the upper urinary tract. METHODS: The expression of p53 protein, Ki-67 antigen, MMP-2 and MMP-9 was examined by immunohistochemistry in 69 patients with TCC of the upper urinary tract. Correlation of p53, Ki-67, MMP-2 and MMP-9 over-expression with conventional pathological parameters and patient survival was examined. RESULTS: p53 over-expression was significantly correlated with histological grade (P < 0.05), but not with pathological stage, vascular invasion, lymphatic invasion or lymph node metastasis. Ki-67 over-expression was significantly correlated with stage, grade, lymphatic invasion and vascular invasion (P < 0.05). In survival analyses, Ki-67 over-expression was a significant prognostic factor in the univariate analysis (P < 0.05), but it did not have a significant impact on survival in the multivariate analysis. Ki-67 labeling index was a significant prognostic factor in patients with a low p53 labeling index, but not in patients with a high p53 labeling index. CONCLUSION: Ki-67 over-expression is of prognostic value in TCC of the upper urinary tract, while p53, MMP-2 and MMP-9 are of limited value.     

Prostate biopsies from black men express higher levels of aggressive disease biomarkers than prostate biopsies from white men

A wide array of biomarkers is being investigated as predictors of prostate cancer (PCa) diagnosis and recurrence. We compared the expression of a small panel of these biomarkers as a function of race among men undergoing radical prostatectomy (RP). Prostate needle biopsy specimens from 131 patients treated with RP at the Durham Veterans Affairs Medical Center were hematoxylin and eosin stained and immunofluorescent assayed for α-methylacyl CoA racemase (AMACR), androgen receptor (AR) and Ki67. Proprietary image analysis was used to identify six biometric feature combinations that were significantly associated with progression in a previous study. Analysis of population characteristics, stratified by race, was performed using rank-sum and χ(2)-test. The effect of race on expression of these biomarker profiles was analyzed using multivariate linear regression. All six biomarker features were expressed at higher levels in black men than white men, with Norm AR (P=0.006) and Ki67 (P=0.02) attaining statistical significance. On multivariate analysis, all markers were expressed at higher levels in black men, with Norm AR (P=0.001), Ki67 (P=0.007) and Ki67/lum (P=0.022) reaching significance. These data support the hypothesis that PCa may be biologically more aggressive among black men.     

Prognostic significance of tumor markers in colorectal cancer patients: DNA index, S-phase fraction, p53 expression, and Ki-67 index

Risk of colorectal cancer recurrence has traditionally been determined by use of pathologic staging. However, it is apparent that subgroups of patients exist within tumor stages whose clinical behavior differs. This study was undertaken to identify tumor-associated factors that might be predictive of outcome in patients with intermediate stages who will benefit the most from postsurgical adjuvant therapy. Seventy patients with stage II and III colorectal cancer were assessed for DNA indes, S-phase fraction, p53 expression, and Ki-67 index. Tumor recurrence was analyzed by means of nonparametric tests and Cox proportional hazard models incorporating standard clinical and pathologic criteria. Of the four prognostic markers evaluated, Ki-67 index was significantly associated with disease recurrence (P=0.02), whereas DNA index, S-phase fraction, and p53 expression were not. After stratification by tumor stage, significant associations between Ki-67 index and disease recurrence were retained in stage II tumors (P=0.01) but not in stage III tumors (P=0.23). Cox proportional hazard regression analysis indicated that among stage II patients, those with a Ki-67 index >45% were associated with 6.5 times greater risk for disease recurrence than those with a Ki-67 index ≤45%. It was concluded that an elevated Ki-67 index is associated with an increased risk of tumor recurrence in stage II colorectal cancer. Presented at the Thirty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, Calif., May 19–22, 1996.     

Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy

OBJECTIVES: Neuroendocrine (NE) cells in prostate cancer may influence tumor cell proliferation in a paracrine fashion. The aims of this study were to clarify the prognostic value of tumor cell proliferation and NE tumor cell differentiation in prostate cancer after radical prostatectomy, and to compare these parameters with each other. MATERIAL AND METHODS: Specimens were pooled from a total of 528 patients treated with radical prostatectomy without neoadjuvant hormonal therapy between 1996 and 2003. NE differentiation (NED) was determined by immunohistochemistry using antibodies directed against chromogranin A (CgA), and was scored as either NE-negative (0-1+) or -positive (2-3+). Tumor cell proliferation was assessed by means of the Ki-67 labeling index (Ki-67 LI). The mean post-surgical follow-up period was 49 months (range 10-116 months). Any subsequent rise in prostate-specific antigen (PSA) level was regarded as reflecting disease progression. The prognostic values of Ki-67 and CgA were comparatively analyzed using multivariate Cox regression. RESULTS: NED was present in 6.1% of tumors. The mean Ki-67 LI was significantly higher in the CgA-positive group in comparison with CgA-negative specimens (6.6% vs 5.0%; p=0.029). The Ki-67 LI showed the highest correlations with Gleason score and pathological tumor stage (r=0.31 and r=0.3, respectively). NED was found to have the strongest association with pathological tumor stage (r=0.2). Multivariate analysis determined Gleason score > or =7 (4+3) [hazard ratio (HR) 3.04], NED (HR 1.89), lymph node metastases (HR 1.84), preoperative PSA level>20 ng/ml (HR 1.66), and Ki-67 LI > or = 5% (HR 1.62) to be significant predictors of biochemical progression. CONCLUSION: Our results identify Ki-67 LI and NED as additional prognostic markers after radical prostatectomy.     

Immunohistochemical Analysis of Radical Prostatectomy Specimens After 8 Months of Neoadjuvant Hormonal Therapy

Neoadjuvant hormone therapy (NHT) prior to radical prostatectomy (RP) results in residual foci of atrophic glands, which can be difficult to identify with hematoxylin-eosin staining, raising the possibility that the low positive-margin rates are an artifact of pathologic understaging. The purpose of this study was to evaluate changes in prostate specific antigen (PSA) and prostatic acid phosphatase (PAP), as well as proliferation marker Ki-67 and Bcl-2 oncoprotein, by immunostaining after 8 months of NHT. Twenty-nine men with clinically confined prostate cancer who received 8 months of NHT and had both pretreatment biopsy and RP specimens obtained at Vancouver Hospital constituted the treatment group. The control group consisted of 23 RP specimens from patients not receiving NHT. Sections were stained with antibodies against PSA, PAP, proliferation marker Ki-67, and the antiapoptosis protein Bcl-2. The PSA and PAP immunostaining were graded for percentage of positive tumor cells and intensity of staining, while Ki-67 and Bcl-2 staining was graded according to the percentage of positive tumor cells. Absent or low percentage-positive PSA and PAP staining was observed in 40% to 50% of the NHT-treated RP specimens but none of the needle biopsy or untreated control RP specimens. Low-intensity PSA and PAP staining was detected only in RP specimens after NHT treatment, and then in only 20% of cases. Low or absent Ki-67 staining was noted in 78% of the NHT- treated RP specimens, compared with only 13% of the matched pre-NHT needle biopsies and 26% of untreated RP specimens. The percentage of specimens with high (>5%) Ki-67 staining decreased from 37% in the pre-NHT needle biopsies to 8% in the NHT-treated RP specimens. Bcl-2 staining increased after treatment with NHT, with 20% of the needle biopsies having high (>5%) Bcl-2 staining compared with 53% of the NHT-treated RP specimens. The frequency of low Bcl-2 staining (<1%) decreased from 53% in the pre-NHT needle biopsies to 27% in the NHT-treated RP specimens. Although PAP and PSA staining decreased after NHT, both markers remain sufficiently positive to be used as epithelial markers to help detect residual foci of prostate cancer that are difficult to identify on H&E-stained slides after NHT. Increased Bcl-2 after NHT, even in early-stage disease, is consistent with its role in the prevention of apoptosis and progression to androgen independence. Low levels of Ki-67 staining indicates a low probability of proliferation and outgrowth of androgen-independent clones after 8 months of NHT.     

The significance of microscopic bladder neck invasion in radical prostatectomies: pT4 disease?

Introduction  It is controversial whether microscopic invasion of the bladder neck (BN) has a high risk for biochemical progression following radical prostatectomy (RP). The tumor, node, and metastasis (TNM) classification for prostate cancer considers BN involvement to be pT4 disease, equivalent to rectal or external sphincter invasion, however, it does not specify whether the invasion is macroscopic or microscopic. Materials and methods  Clinicopathological findings were studied from 290 patients submitted to RP. The time to biochemical (prostate-specific antigen, PSA) progression-free outcome for patients with BN invasion was compared to patients with extraprostatic extension (EPE) or seminal vesicle invasion (SVI). A univariate Cox proportional hazards model was created and a final multivariate Cox proportional hazards model was developed to assess the influence of several variables simultaneously. Results  BN invasion was present in 55/290 (18.96%) surgical specimens and 18/290 (6.2%) also showed positive surgical margins. Patients with microscopic BN invasion had significantly higher preoperative PSA, higher Gleason score, higher apical and circumferential positive surgical margins, more advanced pathological stage, and more extensive tumors. At 5 years 42%, 40%, and 27% of the patients with BN invasion, extraprostatic extension (EPE), and seminal vesicle invasion (SVI), respectively, were free of biochemical recurrence following RP. In multivariate analysis, BN invasion did not contribute for a higher relative hazard of PSA recurrence when added to EPE or SVI. Conclusion  BN invasion is associated with adverse clinicopathological findings. However, the biochemical-free outcome following RP is similar to patients with EPE but significantly better than patients with SVI. The findings of this study do not favor considering microscopic bladder neck invasion as stage pT4 but, probably, stage pT3a.