基于10年PSA检测及前列腺穿刺活检系列研究
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摘要
研究目的(1)建立基于中国人群的前列腺穿刺活检阳性风险预测模型；(2)探讨移行带前列腺特异性抗原(prostate-specific antigen, PSA)密度(TZPSAD)在PSA4.0～10.0和10.1～20.0ng/ml时诊断前列腺癌的作用；(3)年龄≤50岁非前列腺癌男性初始PSA及PSA速度的分布特点分析；(4)前列腺体积(PV)在PSA10.0～50.0ng/ml时对前列腺癌诊断的预测作用；(5)探讨f/tPSA (free/total PSA, f/t PSA)在PSA4.0～20.0ng/ml时诊断前列腺癌的作用。
材料与方法(1)回顾性分析1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者行前列腺穿刺活检,12例患者行2次或2次以上的前列腺穿刺活检,152例患者没有完整的穿刺资料,这些患者被剔除,总共剩下535例患者入选本研究,这些患者当中,486(90.8%)行13点穿刺,28例(5.2%)行6点穿刺,21例行4-15点穿刺(除了6点和13点)。2006年6月之前,采用Abbott Axsym全自动免疫荧光分析(美国雅培公司生产)对患者的进行PSA检测,2006年6月后采用Roche Elecsys2010免疫分析仪(瑞士罗氏公司生产)进行PSA检测。前列腺穿刺活检指征：PSA≥10ng/ml、直肠指检阳性(直肠指检发现前列腺质地硬或结节等)、PSA4～10ng/ml时根据临床医生经验和患者的意愿决定是否行前列腺穿刺活检。PV按下列公式计算：PV(m1)=0.52×前后径(cm)×左右径(cm)×上下径(cm),分析指标包括：年龄、PSA、 PV、直肠指检、f/t PSA、经直肠B超(前列腺外周带发现低回声定义为“阳性”,其他的发现定义为“阴性”)。用逐步回归分析法来确定哪一种指标可以作为前列腺穿刺活检阳性的独立预测因子。在逐步回归分析当中P值没达到0.05的参数则从模型中剔除,可作为独立预测因子的参数用来建立前列腺穿刺活检阳性风险的预测模型。随机抽取100例患者并用Harrell's一致性指数验证建立预测模型的准确性。用受试者操作特征(receiver-operating characteristic, ROC)曲线来评估预测模型和单独PSA预测前列腺穿刺活检阳性风险的准确性。统计学分析采用R软件2.13.1版本(http://www.r-project.org/)。(2)回顾性分析1999年11月至2010年8月在我院行前列腺穿刺活检的患者,共有607例患者前列腺穿刺活检,384例有PSA及前列腺移行带体积完整资料,其中189例PSA4.0-20.0ng/ml,其中183例行13点穿刺,5例行6点穿刺,1例行14点穿刺,这些患者入选本研究。经直肠B超检测前列腺移行带体积(TZV)按下列公式计算：TZV (ml)=0.52×前后径(cm)×左右径(cm)×上下径(cm)；TZPSAD(ng/ml/ml)=PSA (ng/ml)÷TZV (ml)。PSA检测和前列腺穿刺指征如第一章。用接受者操作特性(ROC)曲线计算比较PSA和TZPSAD在诊断前列腺癌的效力。分析PSA和TZPSAD不同临界点在PSA4.0～10.0和10.1～20.0ng/ml范围内对前列腺癌的诊断效力。各临界点预测前列腺癌的总效力为：临界点总效力=临界点敏感性×临界点特异性,临界点总效力最大者被认为最佳临界点。采用SPSS17.0软件处理数据。数值以x±s表示,数值间比较采用t检验和X2检验,a=0.05。(3)回顾性分析2001年1月至2009年11月在我院行第一次PSA检测的患者,其中年龄小于或等于50岁者4211例。11例行前列腺穿刺活检,5例诊断为前列腺恶性肿瘤者被排除,非前列腺癌者4206例和417例PSA检测≥2次入选本研究。PSA检测和前列腺穿刺指征如第一章。利用所有的PSA进行线性回归(linear regression)分析进行PSA速度的计算,公式为：p=at+b,p为PSA值,t为PSA检测的时间(年),α为回归直线的斜率(相当于PSA速度),b为检测时间为零时的截距。以“异常”的初始PSA(1.0、2.5、4.0ng/ml)及“异常"PSA速度(0.35、0.75、2.0ng/ml/year)为临界点,分析不同年龄组(≤30、31-39和40-50岁)初始PSA>1.0、≥2.5、≥4.0ng/ml和PSA速度≥0.35、≥0.75及≥2.0ng/ml/year所占的比例。用直方图描述年龄≤50岁的年轻男性初始PSA及PSA速度的分布情况。研究初始PSA与初始PSA年龄、初始PSA年龄及PSA速度、初始PSA与PSA速度之间有无相关性。采用SPSS17.0软件处理数据。用生存曲线和log-rank检验评估初始PSA高于和低于中位数两组患者将来PSA超过异常范围(2.5ng/ml)风险的差异性。(4)从广州市第一人民医院检索了1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者前列腺穿刺活检,其中593例患者(84.8%)行13点穿刺活检,40例(5.7%)行6点穿刺,66例(9.4%)行4-15点(除6点和13点)穿刺活检,为了减少穿刺针数对前列腺穿刺活检阳性率的影响,只有593例行前列腺13点穿刺活检的患者作为研究对象,这些患者当中,261例具有完整的前列腺体积资料并且PSA在10.0～50.0ng/ml者入选本研究。PSA检测、前列腺穿刺指征、前列腺体积计算公式如第一章。临床分析参数包括：年龄、PSA、PV、直肠指检。为了增加统计结果的可靠性,在统计模型中,前列腺体积作为连续变量和分类变量进行运算(分类变量时中位前列腺体积60m1做为截点),年龄和PSA做为连续变量,直肠指检做为分类变量。采用多元逐步回归分析来评估行前列腺穿刺活检时的前列腺体积及其他参数能否作为预测前列腺癌的发生风险的预测因子。同时,以前列腺体积中位数(本组患者前列腺体积的中位数为60mls)作为临界值,计算不同范围的PSA及不同的直肠指检结果(阴性或阳性)前列腺癌患者比率。采用SPPS18.0版本进行统计,所有检验都是双侧性的,P<0.05被认为具有统计学意义。(5)从广州市第一人民医院检索了1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者前列腺穿刺活检,其中593例患者(84.8%)行13点穿刺活检,40例(5.7%)行6点穿刺,66例(9.4%)行4-15点(除6点和13点)穿刺活检。这些患者当中,531例(76.0%)的患者具有f/t PSA的资料,其中251例(35.9%)总PSA在4.0-20.0ng/ml范围内者入选本研究。PSA检测和前列腺穿刺指征如第一章。f/t PSA的计算：f/t PSA=游离PSA(free PSA, f PSA)÷总PSA (total PSA, t PSA)×100,用接受者操作特性(ROC)曲线分别计算比较PSA4.0～10.Ong/ml、10.1～20.0ng/ml和PSA4.0～20.0ng/ml时f/t PSA和PSA诊断前列腺癌的效力。各临界点预测前列腺癌的总效力为：临界点总效力=临界点敏感性×临界点特异性,临界点总效力最大者被认为最佳临界点。采用SPSS17.0软件处理数据。数值以x±s表示,数值问比较采用t检验,PSA4.0～10.0ng/ml和10.1～20.0ng/ml前列腺癌的诊断率比较采用X2检验,用ROC曲线分析比较PSA和f/t PSA在诊断前列腺癌的总效力,并取各最佳截点进行分析比较。α=0.05。
结果(1)本组患者当中,41.7%(223/535)的患者诊断为前列腺癌。患者PSA的中位数和均数分别为：18.6和91.4ng/ml。前列腺癌患者中位PSA值明显高于非前列腺癌患者(43.4vs.13.1ng/ml, P<0.001),在多因素分析模型中,只有年龄、PSA、PV、DRE可作为独立的预测因子,利用这些独立因子建立的前列腺癌阳性率预测模型公式如下：
建立的风险预测模型经检验,其一致性指数为：0.848,模型和单独PSA预测前列腺穿刺活检阳性曲线下面积分别为84.8%和79.7%。(2)189例前列腺穿刺活检的患者,其中78例PSA4.0～10.0ng/ml,111例PSA10.1～20.0ng/ml,总共40例(21.2%)诊断为前列腺癌,其中PSA4.0～10.0ng/ml者16例(20.5%),PSA10.1～20.0ng/ml者24例(21.6%),前列腺癌在PSA4.0-10.0(?)(?)10.1～20.0ng/ml之间的诊断率差异无统计学意义(P=0.854)。前列腺癌和非前列腺癌患者年龄、前列腺移行带体积之间差异无统计学意义(P值分别为0.680和0.293)；前列腺癌和非前列腺癌患者TZPSAD和直肠指检阳性例数之间差异有统计学意义(P值分别为0.004和0.026)。PSA和TZPSAD在PSA4.0～10.0ng/ml时预测前列腺癌ROC曲线下面积分别为0.569和0.702,PSA7.0ng/ml为最佳临界点,其诊断总效力为30.8%,特异性和敏感性分别为56.2%和54.8%；TZPSAD0.370ng/ml/ml为最佳临界点,其诊断总效力为49.9%,特异性和敏感性分别为68.8%和72.6%,即如果以PSA7.0ng/ml为穿刺活检的临界值,则诊断前列腺癌的敏感性为56.2%(9/16),穿刺活检的阳性率为24.3%(9/37),以TZPSAD0.370ng/ml/ml为穿刺活检的临界值,则诊断前列腺癌的敏感性68.8%(11/16),但前列腺穿刺活检阳性率达到了39.3%(11/28),至少9人免于不必要的前列腺穿刺活检；PSA和TZPSAD在PSA10.1～20.0ng/ml时预测前列腺癌ROC曲线下面积分别为0.463和0.730,PSA13.3ng/ml为最佳临界点,其诊断总效力为23.7%,特异性和敏感性分别为66.7%和35.6%；TZPSAD0.500ng/ml/ml为最佳临界点,其诊断总效力为49.6%,特异性和敏感性分别为70.8%和70.1%,即如果以PSA最佳临界值13.3ng/ml为穿刺活检临界点,则PSA诊断前列腺癌的敏感性为66.7%(16/24),前列腺癌的诊断阳性率仅为21.9%(16/73),但以TZPSAD最佳临界值0.500ng/ml/ml作为穿刺活检的临界点,前列腺癌诊断的敏感性为70.8%(17/24),前列腺癌诊断阳性率提高到39.7%(17/43),至少30人可免于不必要的前列腺穿刺活检。(3)4206例年龄≤50岁的年轻男性,中位初始PSA为0.6ng/ml,被认为“异常”初始PSA者,1026例(24.4%)≥1.0ng/ml,177例(4.2%)≥2.5ng/ml,90例(2.1%)≥4.0ng/ml。绝大部分年轻男性初始PSA分布于0.0-1.0ng/ml和1.1-2.0ng/m1范围之间(分别占75.8%和18.1%)。417例检测2次或2次以上PSA者,中位PSA速度为0.03ng/ml/year,被认为“异常”的PSA速度者,25例(6.0%)≥0.35ng/ml/year,13例(3.1%)≥0.75ng/ml/year,8例(1.9%)≥2.0ng/ml/year。分别有79.1%、10.0%和5.3%的年轻男性PSA速度分布在0.0-0.1ng/ml/year、0.11-0.2ng/ml/year和0.21-0.3ng/ml/year;之间,而仅有极少数PSA速度超过这个范围。417例年龄≤50岁的年轻男性,初始PSA与初始PSA年龄、初始PSA年龄及PSA速度、初始PSA与PSA速度之间均无显著相关(相关系数r分别为：0.077、-0.011和-0.008,P值分别为：0.115、0.831和0.875)。395例初始PSA<2.5ng/ml者,初始PSA检测后,经过最长7.1年的随访,初始PSA高于和低于中位数两组患者将来PSA超过异常范围(2.5ng/ml)的风险差异有统计学意义(log-rank检验,P<0.001)。(4)入选的261例患者中,95(36.4%)被诊断为前列腺癌。本组患者前列腺体积的中位数和均数分别为60和68ml,PSA的中位数和均数分别为19.3和22.3ng/ml.前列腺癌患者的中位年龄、中位PSA及直肠指检的阳性率均高于非前列腺癌患者(所有P值均<0.05),但前列腺体积在前列腺癌患者明显较非前列腺癌患者小(P<0.001)。在多因素逐步回归分析的模型中,相比于其他指标,前列腺体积是前列腺癌发生风险最强的预测指标(OR值为0.02,P<0.001)。当患者PSA水平为10-19.9ng/ml时,前列腺体积小于60mls组和不小于60mls组的前列腺癌检出率分别为40.6%和15.1%,但当患者PSA水平为20-50ng/ml时,两组的前列腺癌检出率分别为65.1%和26.8%。直肠指检阳性的患者,前列腺体积小于60m1s组和不小于60mls组的前列腺癌检出率分别为71.9%和35.3%,直肠指检阴性的患者,前列腺体积小于60mls组和不小于60mls组的前列腺癌检出率分别为41.9和16.7%。(5)251例入选本研究的患者,其中101例PSA4.0～10.0ng/ml,150例PSA10.1～20.0ng/ml,总共58例(23.1%)诊断为前列腺癌,其中PSA4.0～10.0ng/ml者18例(17.8%),PSA10.1～20.0ng/ml者40例(26.7%),但前列腺癌在PSA4.0～10.0和10.1～20.0ng/ml之间的诊断率差异没有统计学意义(P=0.103)。前列腺癌和非前列腺癌患者年龄在PSA4.0～10.0ng/ml者比较具有统计学差异(P=0.033),但在PSA10.1～20.0ng/ml者比较没有统计学差异(P=0.124)；前列腺癌和非前列腺癌患者PSA值在PSA4.0～10.0和10.1～20.Ong/ml两组患者的比较均没有统计学差异(P值分别为0.361和0.435)；前列腺癌f/t PSA和前列腺体积在PSA4.0～10.0和10.1～20.0ng/ml两组患者均较和非前列腺癌患者小,差异均具有统计学意义(P值均小于0.05)。无论是在PSA4.0～10.0ng/ml或是10.1～20.0ng/ml组,前列腺癌的诊断率都随着f/t PSA的降低而升高,当f/tPSA<10%时,前列腺癌的诊断率在PSA4.0～10.0和10.1～20.0ng/ml组分别为46.7%和40.0%；而当f/t PSA>25.0%时,前列腺癌的诊断率在PSA4.0～10.0和10.1～20.0ng/ml组分别仅为11.1%和11.8%。但是,在PSA4.0～1O.0ng/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.569和0.305；在PSA10.1～20.0ng/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.458和0.358；在PSA4.0～20.Ong/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.553和0.325。在PSA4.0～10.0ng/ml时,PSA8.2ng/ml(?)为最佳临界点,其诊断总效力为33.2%,敏感性和特异性分别为50.0%和66.3%；f/t PSA18%为最佳临界点,其诊断总效力为15.4%,敏感性和特异性分别为27.8%和55.4%；在PSA10.1～20.0ng/ml时,PSA15.5ng/ml为最佳临界点,其诊断总效力为23.3%,敏感性和特异性分别为40.0%和58.2%；f/t PSA12%为最佳临界点,其诊断总效力为19.1%,敏感性和特异性分别为52.5%和36.4%；在PSA4.0～20.0ng/ml时,PSA10.5ng/ml为最佳临界点,其诊断总效力为29.9%,敏感性和特异性分别为62.1%和48.2%；f/tPSA12%为最佳临界点,其诊断总效力为15.0%,敏感性和特异性分别为53.4%和28.0%；在上述PSA范围内,如果以f/t PSA的最佳临界点和PSA的最佳临界点相比,其诊断前列腺癌的效力都未增加。
结论(1)我们建立的前列腺穿刺活检阳性风险预测模型在中国人群可达到较为满意的水平,运用此模型来作为医生和患者确定该不该行前列腺穿刺活检的参考工具,最终可达到提高前列腺穿刺活检阳性率的目的。(2)TZPSAD在PSA4.0～10.0和10.1～20.0ng/ml时诊断前列腺癌的效力均明显优于PSA,可明显提高PSA诊断前列腺癌的阳性率,减少不必要的前列腺穿刺活检。(3)年龄≤50岁非前列腺癌男性的中位初始PSA和PSA速度分别为：0.6ng/ml和0.03ng/ml/year。初始PSA高于中位数的患者将来PSA超过2.5ng/ml的风险明显增高。(4)当患者PSA水平为10-50ng/ml时,前列腺体积是前列腺癌的一个独立预测指标。在临床实践中,特别是对于前列腺癌发生率更低的国家,当评估PSA水平处于10-50ng/ml患者的前列腺癌发生风险时,应充分重视前列腺体积的作用。(5)f/t PSA相对于PSA,在PSA4.0～10.0和PSA10.1～20.0ng/ml范围内均不能提高前列腺癌的诊断效力。
OBJECTIVE (1) To develop a nomogram for predicting the probability of a positive initial prostate biopsy in a Chinese population.(2) To assess the efficiencies of transition zone prostate-specific antigen (PSA) density (TZPSAD) in the diagnosis of prostate cancer in Chinese men with PSA of both4.0-10.0and10.1-20.0ng/ml.(3) To explore the distributions and characteristics of initial PSA and PSA velocity in men≤50years old without prostate cancer.(4) To evaluate the association between prostate volume (PV) and prostate cancer detection rate in men with a PSA of10-50ng/ml.(5) To evaluate the efficiency of free/total (f/t) PSA in diagnosis of prostate cancer in Chinese men with PSA4.0-10.0and10.1-20.0ng/ml.
MATERIALS AND METHODS (1) A total of699men who had undergone trans-rectal ultrasound (TRUS)-guided prostate biopsy for the detection of cancer between November1999and June2011were retrieved from our hospital. Twelve men who were biopsied more than2times and152men without complete data were excluded. This left a total of535subjects who were included in the study. Within this cohort,486(90.8%) underwent a13-core biopsy,28(5.2%) underwent a6-core biopsy, and21(3.9%) underwent a4-15core biopsy (not a6-or13-core).PSA was analysed with the Abbott AxSYM PSA (Abbott Corporation) assay before2006and the Roche Elecsys2010PSA assay (Roche Diagnostics) after2006. Prostate volume (PV) was determined during TRUS and was calculated using the formula, PV (ml)=0.52×anterior-posterior diameter (cm)×transverse diameter (cm)×superior-inferior diameter (cm). Age, PSA, PV, digital rectal examination (DRE) status, f/t PSA and TRUS findings (low-echogenicity in the peripheral zone was defined as positive) were included in the stepwise regression analysis. Variables that did not reach statistical significance at a level of0.05were removed from the model in the backward stepwise process. The independent variables from the final model were used to construct a nomogram to predict the probability of a positive initial biopsy. The nomogram was validated and predictive accuracy calculated using Harrell's Concordance Index C on100bootstrapped re-samples. A Receiver operating characteristic (ROC) curve was used to evaluate the effectiveness of the nomogram and PSA alone in predicting a positive initial prostate biopsy. Statistical analyses were performed with R version2.13.1(http://www.r-project.org/).(2) A total of607men who had undergone trans-rectal ultrasound-guided systematic prostatic biopsy for detecting prostate cancer from November1999to August2009were retrieved from our hospital. Of the607men who had a prostatic biopsy,384had a document of trans-rectal ultrasound transition zone and PSA measurements. A total of189men with a biopsy PSA of4.0-20.0ng/ml were included in the study. Of these men,183,5,1had undergone13,6, and14systematic cores prostatic biopsy, respectively. PSA measurement and prostatic biopsy were performed as Chapter (1). Prostate transition zone volume (TZV) was calculated using the following formula:TZV (ml)=0.52×anterior-posterior diameter (cm)×transverse diameter (cm)×superior-inferior diameter (cm). TZPSAD (ng/ml/ml)=PSA (ng/ml)÷TZV (ml). A ROC curve was used to compare the efficiency of PSA and TZPSAD in the diagnosis of prostate cancer in men with a PSA of4.0-10.0and10.1-20.0ng/ml.The efficiencies in the diagnosis of prostate cancer for different PSA and TZPSAD cut-offs in men with PSA4.0-10.0and10.1-20.0ng/ml were also evaluated. Total efficiency in the diagnosis of prostate cancer for different PSA and TZPSAD cut-offs was calculated using the following formula:total efficiency=sensitivity x specificity. The cut-off of the greatest efficiency on the ROC curve was considered as best cut-off for diagnosis of prostate cancer. Student-t test was used to compare the differences of age, PSA, TZV, and TZPSAD between prostate cancer and non-prostate cancer group. Chi square test was used to compare the detection rate of prostate cancer between PSA4.0-10.0and10.1-20.0ng/ml group. Statistical analyses were performed using SPSS program (version17.0, Chicago, IL). All statistical tests were two-sided with a P<0.05considered statistically significant.(3) A total of4211men had their initial PSA measurement at age≤50years old from January2001to November2009were retrospectively retrieved from our hospital. Of these men,11had undergone prostatic biopsy and5were diagnosed with prostate cancer. Those with a diagnosis of prostate cancer were excluded. This left4206men were included in the study. Of these men, PSA velocity was calculated in417who had their PSA measurement twice or more. PSA measurement and prostatic biopsy were performed as Chapter (1). PSA velocity was calculated as the slope of linear regression line of all PSA values collected over time. The important cutoffs of baseline PSA (1.0,2.5and4.0ng/ml) and PSA velocity (0.35,0.75,1.0ng/ml/year) were used to stratify patients in different age groups (≤30,31-39, and40-50years old). The differences of baseline PSA and PSA velocity and the correlation of baseline PSA and PSA velocity were assessed. The distributions of baseline PSA and PSA velocity in men age≤50years old were demonstrated. The correlations between initial PSA, initial PSA age, and PSA velocity were also estimated. Kaplan-meier and log-rank test were used to estimate the significant difference at the risk of PSA≥2.5ng/ml after initial PSA measurement, stratified by median initial PSA (0.6ng/ml).(4) A total of699men who had undergone TRUS guided prostate biopsy between November1999and June2011were retrieved from our hospital. Within this cohort,593(84.8%) underwent13-core biopsy,40(5.7%) underwent6-core biopsy and66(9.4%) underwent4-15core biopsy (not6or13cores). Two hundreds and sixty one men with a PSA of10-50ng/ml underwent a13-core prostate biopsy with complete PV data were included in the study. PV was measured via TRUS. PSA measurement, prostatic biopsy, and PV calculation were performed as Chapter (1). The clinical variables included in analysis were age at prostate biopsy, PSA at time of biopsy, PV, and DRE status. PV was used as both a continuous and categorical variable (stratified by median). Age and PSA were analyzed as a continuous variable and DRE was treated as a categorical variable. Multivariate stepwise Logistic regression was used to determine which variables (PV as a continuous or categoric variable, age and PSA as a continuous variable, and DRE as a categoric variable) were predictive of a positive TRUS biopsy. The rates of prostate cancer among men with different DRE statuses and PSA ranges, stratified by PV medians, were calculated. Statistical analyses were performed using SPSS statistical software (version18.0; SPSS Inc,Chicago, IL). All statistical tests were2-sided with a P<0.05considered to be statistically significant.(5) A total of699men who had undergone trans-rectal ultrasound-guided systematic prostatic biopsy for detecting prostate cancer from November1999to June2011were retrieved from our hospital. Of the699men who had a prostatic biopsy,251had a document of free to total PSA measurements with a biopsy PSA of4.0-20.0ng/ml were included in the study. PSA was analyzed with the following assays:PSA measurement and prostatic biopsy were performed as Chapter (1). f/t PSA was calculated using the following formula:f/t PSA=f PSA (ng/ml)÷t PSA (ng/ml). Receiver operating characteristic (ROC) curve was used to compare the efficiency of PSA and f/t PSA in the diagnosis of prostate cancer in men with a PSA of4.0-10.0and10.1-20.0ng/ml. The efficiencies in the diagnosis of prostate cancer for PSA and f/t PSA best cut-offs in men with PSA4.0-10.0and10.1-20.0ng/ml were also evaluated. Total efficiency in the diagnosis of prostate cancer for PSA and f/t PSA best cut-offs was calculated using the following formula:total efficiency=sensitivity x specificity. The cut-off of the greatest efficiency on the ROC curve was considered as best cut-off for diagnosis of prostate cancer. Student-t test was used to compare the differences of age, PSA, PV, and F/T PSA between prostate cancer and non-prostate cancer group. Chi square test was used to compare the detection rate of prostate cancer between PSA4.0-10.0and10.1-20.0ng/ml group. Statistical analyses were performed using SPSS program (version17.0, Chicago, IL). All statistical tests were two-sided with a P<0.05considered statistically significant.
RESULT (1) Of the535subjects included in the study,41.7%(223/535) had a positive initial prostate biopsy. The median and mean diagnostic PSA levels in our study cohort were18.6and91.4ng/ml, respectively. The median PSA level in men with a positive initial prostate biopsy was statistically higher than those with a negative biopsy (43.4Vs.13.1ng/ml, P<0.001, Mann-Whitney U test). In a multivariate analysis, only age, PV, LogPSA, and DRE were found to be independent predictors of a positive initial prostate biopsy.The logistic regression model yielded the equation below:
Positive initial prostate biopsy probability equation for Chinese population=
e-1.163+0.033Age+1.032DRE-2.821LogePV+2.292LogPSA
1+e-1.163+0.033Age+1.032DRE-2.821LogPV+2.292LogPSA
Using the information from multivariate regression analysis, a nomogram model was developed that allows the calculation of an individual patient's risk for a positive initial prostate biopsy. A concordance index of0.848, representing predictive accuracy, was found upon internal validation of the nomogram.Our nomogram was superior in predictive accuracy to that with diagnostic PSA data, increasing the area under the curve (AUC) from79.7%to84.8%.(2) Of the189men included in the study,78and111had a PSA of4.0-10.Ong/ml and10.1-20.0ng/ml, respectively. A total of40patients (21.2%) were diagnosed with prostate cancer. In78men with a PSA of4.0-10.0ng/ml,16(20.5%) were diagnosed with prostate cancer. In111men with a PSA of10.1-20.0ng/ml,24(21.6%) were diagnosed with prostate cancer. The rate of prostate cancer between men with a PSA of4.0-10.0and10.1-20.0ng/ml groups was not statistically different (P=0.854). The differences of age, prostate transition zone volume between prostate cancer and non-prostate cancer groups were both not statistically significant different (P=0.680and0.293, respectively). The TZPSAD and rate of positive digital rectal examination between prostate cancer and non-prostate cancer groups were both statistically different (P=0.004and0.026, respectively). The areas under the ROC curve (AUCs) for PSA and TZPSAD as continuous variables in predicting prostate cancer in men with a PSA of4.0-10.0ng/ml were0.569and0.702, respectively. When the best PSA cut-off of7.0ng/ml was chosen to predict prostate cancer, the total efficiency was30.8%and corresponding specificity and sensitivity were56.2%and54.8%, respectively. For the best TZPSAD cut-off of0.370ng/ml/ml, the total efficiency was49.9%and the corresponding specificity and sensitivity were68.8%and72.6%, respectively. If PSA7.0ng/ml was chosen for the biopsy cut-off,56.2%(9/16) of the prostate cancer could be diagnosed and the positive biopsy rate was24.3%(9/37). However, if TZPSAD0.370ng/ml/ml was chosen for the biopsy cut-off,68.8%(11/16) of the prostate cancer could be diagnosed and the positive rate of prostate biopsy was up to39.3%(11/28). At least9men could avoid unnecessary prostate biopsy. The AUCs for PSA and TZPSAD as continuous variables in predicting prostate cancer in men with a PSA of10.1-20.0ng/ml were0.463and0.730, respectively. When the best PSA cut-off of13.3ng/ml was chosen to predict prostate cancer, the total efficiency was23.7%and corresponding specificity and sensitivity were66.7%and35.6%, respectively. For the best TZPSAD cut-off of0.500ng/ml/ml, the total efficiency was49.6%and the corresponding specificity and sensitivity were70.8%and70.1%, respectively. If PSA13.3ng/ml was chosen for the biopsy cut-off,66.7%(16/24) of the prostate cancer could be diagnosed and the positive biopsy rate was21.9%(16/73). But, if TZPSAD0.500ng/ml/ml was chosen for the biopsy cut-off,70.8%(17/24) of the prostate cancer could be diagnosed and the positive rate of prostate biopsy was up to39.7%(17/43). At least30men could avoid unnecessary prostate biopsy.(3) A total of4206men without prostate cancer were included. The median initial PSA value in these men was0.6ng/ml. Of these men,1026(24.4%),177(4.2%), and90(2.1%) had a initial PSA of≥1.0≥2.5, and≥4.0ng/ml, respectively. A total of417men had their PSA measurement twice or more. The median PSA velocity in these men was0.03ng/ml/year. Of these men,25(6.0%),13(3.1%), and8(1.9%) had a PSA velocity of≥0.35、≥0.75、≥2.00ng-ml/year,respectively. These were no direct correlations between initial PSA age and initial PSA, initial PSA age and PSA velocity, and initial PSA and PSA velocity (correlation coefficient r=0.077,-0.011and-0.008, respectively; P=0.115,0.831,and0.875, respectively). After a follow-up of up to7.1years from baseline PSA measurement, the risk of PSA≥2.5ng/ml, stratified by median initial PSA (0.6ng/ml) was significantly different (log-rank test, P<0.001).(4) Of the261subjects included in the study,95(36.4%) were diagnosed with prostate cancer. The median and mean PVs in our study cohort were60and68ml, respectively. Median and mean diagnostic PSA in our study cohort were19.3and22.3ng/ml, respectively. The median age, PSA, PV, and rate of positive DRE in men diagnosed with prostate cancer were all statistically significantly higher than those did not have prostate cancer (all p values<0.05). On univariate analysis, the risk of prostate cancer was inversely associated with PV. On stepwise multivariate analysis, PV (as either a continuous or categorical variable), age, PSA, and DRE status were all found to be independent predictors of prostate cancer. Men with a PV of≥60ml (median) were found to be at a decreased risk of having prostate cancer with odds ratios of0.23when compared to those with a PV of <60ml (p value<0.010). The rates of prostate cancer in men with a PV of<60and≥60ml in the PSA of10-19.9ng/ml group were40.6%and15.1%, respectively, while rates for those with a PSA of20-50ng/ml were65.1%and26.8%, respectively. The rates of prostate cancer in for men with a PV of<60or≥60ml and with a positive DRE were71.9%and35.3%, respectively, while the rates for those with a negative DRE saw rates of41.9%and16.7%, respectively.(5) Of the251men included in the study,101and140had a PSA of4.0-10.0ng/ml and10.1-20.0ng/ml, respectively. A total of58patients (23.1%) were diagnosed with prostate cancer. In101men with a PSA of4.0-10.0ng/ml,18(17.8%) were diagnosed with prostate cancer. In140men with a PSA of10.1-20.0ng/ml,40(26.7%) were diagnosed with prostate cancer. The rate of prostate cancer between men with a PSA of4.0-10.0and10.1-20.0ng/ml groups was not statistically different (P=0.103). The differences of f/t PSA and prostate volume between prostate cancer and non-prostate cancer groups were both statistically significant different (all P values<0.05). The PSA between prostate cancer and non-prostate cancer groups were both not statistically different (P=0.361and0.435,respectively).The rates of prostate cancer inversely decreased with f/t PSA increased. Prostate cancer detection rates in men with f/t PSA<10%in PSA4.0-10.0and10.1-20.0ng/ml ranges were46.7%and40.0%, respectively. Whereas, prostate cancer detection rates in men with f/t PSA>25%in PSA4.0-10.0and10.1-20.0ng/ml ranges were only11.1%and11.8%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of4.0-10.0ng/ml were0.569and0.305, respectively. When the best PSA cut-off of8.2ng/ml was chosen to predict prostate cancer, the total efficiency was33.2%and corresponding sensitivity and specificity were50.0%and66.3%, respectively. For the best f/t PSA cut-off of18%, the total efficiency was15.4%and the corresponding sensitivity and specificity were27.8%and55.4%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of10.1-20.0ng/ml were0.458and0.358, respectively. When the best PSA cut-off of15.5ng/ml was chosen to predict prostate cancer, the total efficiency was23.3%and corresponding sensitivity and specificity were40.0%and58.2%, respectively. For the best f/t PSA cut-off of12%, the total efficiency was19.1%and the corresponding sensitivity and specificity were52.5%and36.4%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of4.0-20.0ng/ml were0.553and0.325, respectively. When the best PSA cut-off of10.5ng/ml was chosen to predict prostate cancer, the total efficiency was29.9%and corresponding sensitivity and specificity were62.1%and48.2%, respectively. For the best f/t PSA cut-off of12%, the total efficiency was15.0%and the corresponding sensitivity and specificity were53.4%and28.0%, respectively. In men with PSA4.0-10.0and10.1-20.0ng/ml, the efficiencies of best cutoffs for f/t PSA were not better than best cutoffs for PSA in diagnosis of prostate cancer.
CONCLUSION (1) Our results indicate that the risk of a positive initial prostate biopsy can be predicted to a satisfactory level in a Chinese population using our nomogram. The nomogram can be used to identify and counsel patients who should consider a prostate biopsy, ultimately enhancing accuracy in diagnosing prostate cancer.(2) Using TZPSAD can improve the efficiency of PSA in diagnosis of prostate cancer and decreases the unnecessary prostatic biopsy in men with a PSA of both 4.0-10.0and10.1-20.0ng/ml.(3) The median baseline PSA and PSA velocity in men younger than50years old with prostate cancer are0.6ng/ml and0.03ng/ml/year, respectively. Men younger than50years old without prostate cancer with an initial PSA higher than median (0.6ng/ml) have a subsequently higher risk of PSA value≥2.5ng/ml.(4) PV is an independent predictor of prostate cancer in men with a PSA of10-50ng/ml. In clinical practice, especially for those countries with lower PCa incidence, PV should be taken into account so as to improve the prostate cancer detection rate and avoid unnecessary biopsy.(5) f/t PSA does not improve the efficiency of prostate specific antigen in diagnosis of prostate cancer in Chinese men with PSA4.0-10.0and10.1-20.0ng/ml.
材料与方法(1)回顾性分析1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者行前列腺穿刺活检,12例患者行2次或2次以上的前列腺穿刺活检,152例患者没有完整的穿刺资料,这些患者被剔除,总共剩下535例患者入选本研究,这些患者当中,486(90.8%)行13点穿刺,28例(5.2%)行6点穿刺,21例行4-15点穿刺(除了6点和13点)。2006年6月之前,采用Abbott Axsym全自动免疫荧光分析(美国雅培公司生产)对患者的进行PSA检测,2006年6月后采用Roche Elecsys2010免疫分析仪(瑞士罗氏公司生产)进行PSA检测。前列腺穿刺活检指征：PSA≥10ng/ml、直肠指检阳性(直肠指检发现前列腺质地硬或结节等)、PSA4～10ng/ml时根据临床医生经验和患者的意愿决定是否行前列腺穿刺活检。PV按下列公式计算：PV(m1)=0.52×前后径(cm)×左右径(cm)×上下径(cm),分析指标包括：年龄、PSA、 PV、直肠指检、f/t PSA、经直肠B超(前列腺外周带发现低回声定义为“阳性”,其他的发现定义为“阴性”)。用逐步回归分析法来确定哪一种指标可以作为前列腺穿刺活检阳性的独立预测因子。在逐步回归分析当中P值没达到0.05的参数则从模型中剔除,可作为独立预测因子的参数用来建立前列腺穿刺活检阳性风险的预测模型。随机抽取100例患者并用Harrell's一致性指数验证建立预测模型的准确性。用受试者操作特征(receiver-operating characteristic, ROC)曲线来评估预测模型和单独PSA预测前列腺穿刺活检阳性风险的准确性。统计学分析采用R软件2.13.1版本(http://www.r-project.org/)。(2)回顾性分析1999年11月至2010年8月在我院行前列腺穿刺活检的患者,共有607例患者前列腺穿刺活检,384例有PSA及前列腺移行带体积完整资料,其中189例PSA4.0-20.0ng/ml,其中183例行13点穿刺,5例行6点穿刺,1例行14点穿刺,这些患者入选本研究。经直肠B超检测前列腺移行带体积(TZV)按下列公式计算：TZV (ml)=0.52×前后径(cm)×左右径(cm)×上下径(cm)；TZPSAD(ng/ml/ml)=PSA (ng/ml)÷TZV (ml)。PSA检测和前列腺穿刺指征如第一章。用接受者操作特性(ROC)曲线计算比较PSA和TZPSAD在诊断前列腺癌的效力。分析PSA和TZPSAD不同临界点在PSA4.0～10.0和10.1～20.0ng/ml范围内对前列腺癌的诊断效力。各临界点预测前列腺癌的总效力为：临界点总效力=临界点敏感性×临界点特异性,临界点总效力最大者被认为最佳临界点。采用SPSS17.0软件处理数据。数值以x±s表示,数值间比较采用t检验和X2检验,a=0.05。(3)回顾性分析2001年1月至2009年11月在我院行第一次PSA检测的患者,其中年龄小于或等于50岁者4211例。11例行前列腺穿刺活检,5例诊断为前列腺恶性肿瘤者被排除,非前列腺癌者4206例和417例PSA检测≥2次入选本研究。PSA检测和前列腺穿刺指征如第一章。利用所有的PSA进行线性回归(linear regression)分析进行PSA速度的计算,公式为：p=at+b,p为PSA值,t为PSA检测的时间(年),α为回归直线的斜率(相当于PSA速度),b为检测时间为零时的截距。以“异常”的初始PSA(1.0、2.5、4.0ng/ml)及“异常"PSA速度(0.35、0.75、2.0ng/ml/year)为临界点,分析不同年龄组(≤30、31-39和40-50岁)初始PSA>1.0、≥2.5、≥4.0ng/ml和PSA速度≥0.35、≥0.75及≥2.0ng/ml/year所占的比例。用直方图描述年龄≤50岁的年轻男性初始PSA及PSA速度的分布情况。研究初始PSA与初始PSA年龄、初始PSA年龄及PSA速度、初始PSA与PSA速度之间有无相关性。采用SPSS17.0软件处理数据。用生存曲线和log-rank检验评估初始PSA高于和低于中位数两组患者将来PSA超过异常范围(2.5ng/ml)风险的差异性。(4)从广州市第一人民医院检索了1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者前列腺穿刺活检,其中593例患者(84.8%)行13点穿刺活检,40例(5.7%)行6点穿刺,66例(9.4%)行4-15点(除6点和13点)穿刺活检,为了减少穿刺针数对前列腺穿刺活检阳性率的影响,只有593例行前列腺13点穿刺活检的患者作为研究对象,这些患者当中,261例具有完整的前列腺体积资料并且PSA在10.0～50.0ng/ml者入选本研究。PSA检测、前列腺穿刺指征、前列腺体积计算公式如第一章。临床分析参数包括：年龄、PSA、PV、直肠指检。为了增加统计结果的可靠性,在统计模型中,前列腺体积作为连续变量和分类变量进行运算(分类变量时中位前列腺体积60m1做为截点),年龄和PSA做为连续变量,直肠指检做为分类变量。采用多元逐步回归分析来评估行前列腺穿刺活检时的前列腺体积及其他参数能否作为预测前列腺癌的发生风险的预测因子。同时,以前列腺体积中位数(本组患者前列腺体积的中位数为60mls)作为临界值,计算不同范围的PSA及不同的直肠指检结果(阴性或阳性)前列腺癌患者比率。采用SPPS18.0版本进行统计,所有检验都是双侧性的,P<0.05被认为具有统计学意义。(5)从广州市第一人民医院检索了1999年11月至2011年6月在我院行前列腺穿刺活检的患者,共有699例患者前列腺穿刺活检,其中593例患者(84.8%)行13点穿刺活检,40例(5.7%)行6点穿刺,66例(9.4%)行4-15点(除6点和13点)穿刺活检。这些患者当中,531例(76.0%)的患者具有f/t PSA的资料,其中251例(35.9%)总PSA在4.0-20.0ng/ml范围内者入选本研究。PSA检测和前列腺穿刺指征如第一章。f/t PSA的计算：f/t PSA=游离PSA(free PSA, f PSA)÷总PSA (total PSA, t PSA)×100,用接受者操作特性(ROC)曲线分别计算比较PSA4.0～10.Ong/ml、10.1～20.0ng/ml和PSA4.0～20.0ng/ml时f/t PSA和PSA诊断前列腺癌的效力。各临界点预测前列腺癌的总效力为：临界点总效力=临界点敏感性×临界点特异性,临界点总效力最大者被认为最佳临界点。采用SPSS17.0软件处理数据。数值以x±s表示,数值问比较采用t检验,PSA4.0～10.0ng/ml和10.1～20.0ng/ml前列腺癌的诊断率比较采用X2检验,用ROC曲线分析比较PSA和f/t PSA在诊断前列腺癌的总效力,并取各最佳截点进行分析比较。α=0.05。
结果(1)本组患者当中,41.7%(223/535)的患者诊断为前列腺癌。患者PSA的中位数和均数分别为：18.6和91.4ng/ml。前列腺癌患者中位PSA值明显高于非前列腺癌患者(43.4vs.13.1ng/ml, P<0.001),在多因素分析模型中,只有年龄、PSA、PV、DRE可作为独立的预测因子,利用这些独立因子建立的前列腺癌阳性率预测模型公式如下：
建立的风险预测模型经检验,其一致性指数为：0.848,模型和单独PSA预测前列腺穿刺活检阳性曲线下面积分别为84.8%和79.7%。(2)189例前列腺穿刺活检的患者,其中78例PSA4.0～10.0ng/ml,111例PSA10.1～20.0ng/ml,总共40例(21.2%)诊断为前列腺癌,其中PSA4.0～10.0ng/ml者16例(20.5%),PSA10.1～20.0ng/ml者24例(21.6%),前列腺癌在PSA4.0-10.0(?)(?)10.1～20.0ng/ml之间的诊断率差异无统计学意义(P=0.854)。前列腺癌和非前列腺癌患者年龄、前列腺移行带体积之间差异无统计学意义(P值分别为0.680和0.293)；前列腺癌和非前列腺癌患者TZPSAD和直肠指检阳性例数之间差异有统计学意义(P值分别为0.004和0.026)。PSA和TZPSAD在PSA4.0～10.0ng/ml时预测前列腺癌ROC曲线下面积分别为0.569和0.702,PSA7.0ng/ml为最佳临界点,其诊断总效力为30.8%,特异性和敏感性分别为56.2%和54.8%；TZPSAD0.370ng/ml/ml为最佳临界点,其诊断总效力为49.9%,特异性和敏感性分别为68.8%和72.6%,即如果以PSA7.0ng/ml为穿刺活检的临界值,则诊断前列腺癌的敏感性为56.2%(9/16),穿刺活检的阳性率为24.3%(9/37),以TZPSAD0.370ng/ml/ml为穿刺活检的临界值,则诊断前列腺癌的敏感性68.8%(11/16),但前列腺穿刺活检阳性率达到了39.3%(11/28),至少9人免于不必要的前列腺穿刺活检；PSA和TZPSAD在PSA10.1～20.0ng/ml时预测前列腺癌ROC曲线下面积分别为0.463和0.730,PSA13.3ng/ml为最佳临界点,其诊断总效力为23.7%,特异性和敏感性分别为66.7%和35.6%；TZPSAD0.500ng/ml/ml为最佳临界点,其诊断总效力为49.6%,特异性和敏感性分别为70.8%和70.1%,即如果以PSA最佳临界值13.3ng/ml为穿刺活检临界点,则PSA诊断前列腺癌的敏感性为66.7%(16/24),前列腺癌的诊断阳性率仅为21.9%(16/73),但以TZPSAD最佳临界值0.500ng/ml/ml作为穿刺活检的临界点,前列腺癌诊断的敏感性为70.8%(17/24),前列腺癌诊断阳性率提高到39.7%(17/43),至少30人可免于不必要的前列腺穿刺活检。(3)4206例年龄≤50岁的年轻男性,中位初始PSA为0.6ng/ml,被认为“异常”初始PSA者,1026例(24.4%)≥1.0ng/ml,177例(4.2%)≥2.5ng/ml,90例(2.1%)≥4.0ng/ml。绝大部分年轻男性初始PSA分布于0.0-1.0ng/ml和1.1-2.0ng/m1范围之间(分别占75.8%和18.1%)。417例检测2次或2次以上PSA者,中位PSA速度为0.03ng/ml/year,被认为“异常”的PSA速度者,25例(6.0%)≥0.35ng/ml/year,13例(3.1%)≥0.75ng/ml/year,8例(1.9%)≥2.0ng/ml/year。分别有79.1%、10.0%和5.3%的年轻男性PSA速度分布在0.0-0.1ng/ml/year、0.11-0.2ng/ml/year和0.21-0.3ng/ml/year;之间,而仅有极少数PSA速度超过这个范围。417例年龄≤50岁的年轻男性,初始PSA与初始PSA年龄、初始PSA年龄及PSA速度、初始PSA与PSA速度之间均无显著相关(相关系数r分别为：0.077、-0.011和-0.008,P值分别为：0.115、0.831和0.875)。395例初始PSA<2.5ng/ml者,初始PSA检测后,经过最长7.1年的随访,初始PSA高于和低于中位数两组患者将来PSA超过异常范围(2.5ng/ml)的风险差异有统计学意义(log-rank检验,P<0.001)。(4)入选的261例患者中,95(36.4%)被诊断为前列腺癌。本组患者前列腺体积的中位数和均数分别为60和68ml,PSA的中位数和均数分别为19.3和22.3ng/ml.前列腺癌患者的中位年龄、中位PSA及直肠指检的阳性率均高于非前列腺癌患者(所有P值均<0.05),但前列腺体积在前列腺癌患者明显较非前列腺癌患者小(P<0.001)。在多因素逐步回归分析的模型中,相比于其他指标,前列腺体积是前列腺癌发生风险最强的预测指标(OR值为0.02,P<0.001)。当患者PSA水平为10-19.9ng/ml时,前列腺体积小于60mls组和不小于60mls组的前列腺癌检出率分别为40.6%和15.1%,但当患者PSA水平为20-50ng/ml时,两组的前列腺癌检出率分别为65.1%和26.8%。直肠指检阳性的患者,前列腺体积小于60m1s组和不小于60mls组的前列腺癌检出率分别为71.9%和35.3%,直肠指检阴性的患者,前列腺体积小于60mls组和不小于60mls组的前列腺癌检出率分别为41.9和16.7%。(5)251例入选本研究的患者,其中101例PSA4.0～10.0ng/ml,150例PSA10.1～20.0ng/ml,总共58例(23.1%)诊断为前列腺癌,其中PSA4.0～10.0ng/ml者18例(17.8%),PSA10.1～20.0ng/ml者40例(26.7%),但前列腺癌在PSA4.0～10.0和10.1～20.0ng/ml之间的诊断率差异没有统计学意义(P=0.103)。前列腺癌和非前列腺癌患者年龄在PSA4.0～10.0ng/ml者比较具有统计学差异(P=0.033),但在PSA10.1～20.0ng/ml者比较没有统计学差异(P=0.124)；前列腺癌和非前列腺癌患者PSA值在PSA4.0～10.0和10.1～20.Ong/ml两组患者的比较均没有统计学差异(P值分别为0.361和0.435)；前列腺癌f/t PSA和前列腺体积在PSA4.0～10.0和10.1～20.0ng/ml两组患者均较和非前列腺癌患者小,差异均具有统计学意义(P值均小于0.05)。无论是在PSA4.0～10.0ng/ml或是10.1～20.0ng/ml组,前列腺癌的诊断率都随着f/t PSA的降低而升高,当f/tPSA<10%时,前列腺癌的诊断率在PSA4.0～10.0和10.1～20.0ng/ml组分别为46.7%和40.0%；而当f/t PSA>25.0%时,前列腺癌的诊断率在PSA4.0～10.0和10.1～20.0ng/ml组分别仅为11.1%和11.8%。但是,在PSA4.0～1O.0ng/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.569和0.305；在PSA10.1～20.0ng/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.458和0.358；在PSA4.0～20.Ong/ml时,PSA和f/t PSA预测前列腺癌ROC曲线下面积分别为0.553和0.325。在PSA4.0～10.0ng/ml时,PSA8.2ng/ml(?)为最佳临界点,其诊断总效力为33.2%,敏感性和特异性分别为50.0%和66.3%；f/t PSA18%为最佳临界点,其诊断总效力为15.4%,敏感性和特异性分别为27.8%和55.4%；在PSA10.1～20.0ng/ml时,PSA15.5ng/ml为最佳临界点,其诊断总效力为23.3%,敏感性和特异性分别为40.0%和58.2%；f/t PSA12%为最佳临界点,其诊断总效力为19.1%,敏感性和特异性分别为52.5%和36.4%；在PSA4.0～20.0ng/ml时,PSA10.5ng/ml为最佳临界点,其诊断总效力为29.9%,敏感性和特异性分别为62.1%和48.2%；f/tPSA12%为最佳临界点,其诊断总效力为15.0%,敏感性和特异性分别为53.4%和28.0%；在上述PSA范围内,如果以f/t PSA的最佳临界点和PSA的最佳临界点相比,其诊断前列腺癌的效力都未增加。
结论(1)我们建立的前列腺穿刺活检阳性风险预测模型在中国人群可达到较为满意的水平,运用此模型来作为医生和患者确定该不该行前列腺穿刺活检的参考工具,最终可达到提高前列腺穿刺活检阳性率的目的。(2)TZPSAD在PSA4.0～10.0和10.1～20.0ng/ml时诊断前列腺癌的效力均明显优于PSA,可明显提高PSA诊断前列腺癌的阳性率,减少不必要的前列腺穿刺活检。(3)年龄≤50岁非前列腺癌男性的中位初始PSA和PSA速度分别为：0.6ng/ml和0.03ng/ml/year。初始PSA高于中位数的患者将来PSA超过2.5ng/ml的风险明显增高。(4)当患者PSA水平为10-50ng/ml时,前列腺体积是前列腺癌的一个独立预测指标。在临床实践中,特别是对于前列腺癌发生率更低的国家,当评估PSA水平处于10-50ng/ml患者的前列腺癌发生风险时,应充分重视前列腺体积的作用。(5)f/t PSA相对于PSA,在PSA4.0～10.0和PSA10.1～20.0ng/ml范围内均不能提高前列腺癌的诊断效力。
OBJECTIVE (1) To develop a nomogram for predicting the probability of a positive initial prostate biopsy in a Chinese population.(2) To assess the efficiencies of transition zone prostate-specific antigen (PSA) density (TZPSAD) in the diagnosis of prostate cancer in Chinese men with PSA of both4.0-10.0and10.1-20.0ng/ml.(3) To explore the distributions and characteristics of initial PSA and PSA velocity in men≤50years old without prostate cancer.(4) To evaluate the association between prostate volume (PV) and prostate cancer detection rate in men with a PSA of10-50ng/ml.(5) To evaluate the efficiency of free/total (f/t) PSA in diagnosis of prostate cancer in Chinese men with PSA4.0-10.0and10.1-20.0ng/ml.
MATERIALS AND METHODS (1) A total of699men who had undergone trans-rectal ultrasound (TRUS)-guided prostate biopsy for the detection of cancer between November1999and June2011were retrieved from our hospital. Twelve men who were biopsied more than2times and152men without complete data were excluded. This left a total of535subjects who were included in the study. Within this cohort,486(90.8%) underwent a13-core biopsy,28(5.2%) underwent a6-core biopsy, and21(3.9%) underwent a4-15core biopsy (not a6-or13-core).PSA was analysed with the Abbott AxSYM PSA (Abbott Corporation) assay before2006and the Roche Elecsys2010PSA assay (Roche Diagnostics) after2006. Prostate volume (PV) was determined during TRUS and was calculated using the formula, PV (ml)=0.52×anterior-posterior diameter (cm)×transverse diameter (cm)×superior-inferior diameter (cm). Age, PSA, PV, digital rectal examination (DRE) status, f/t PSA and TRUS findings (low-echogenicity in the peripheral zone was defined as positive) were included in the stepwise regression analysis. Variables that did not reach statistical significance at a level of0.05were removed from the model in the backward stepwise process. The independent variables from the final model were used to construct a nomogram to predict the probability of a positive initial biopsy. The nomogram was validated and predictive accuracy calculated using Harrell's Concordance Index C on100bootstrapped re-samples. A Receiver operating characteristic (ROC) curve was used to evaluate the effectiveness of the nomogram and PSA alone in predicting a positive initial prostate biopsy. Statistical analyses were performed with R version2.13.1(http://www.r-project.org/).(2) A total of607men who had undergone trans-rectal ultrasound-guided systematic prostatic biopsy for detecting prostate cancer from November1999to August2009were retrieved from our hospital. Of the607men who had a prostatic biopsy,384had a document of trans-rectal ultrasound transition zone and PSA measurements. A total of189men with a biopsy PSA of4.0-20.0ng/ml were included in the study. Of these men,183,5,1had undergone13,6, and14systematic cores prostatic biopsy, respectively. PSA measurement and prostatic biopsy were performed as Chapter (1). Prostate transition zone volume (TZV) was calculated using the following formula:TZV (ml)=0.52×anterior-posterior diameter (cm)×transverse diameter (cm)×superior-inferior diameter (cm). TZPSAD (ng/ml/ml)=PSA (ng/ml)÷TZV (ml). A ROC curve was used to compare the efficiency of PSA and TZPSAD in the diagnosis of prostate cancer in men with a PSA of4.0-10.0and10.1-20.0ng/ml.The efficiencies in the diagnosis of prostate cancer for different PSA and TZPSAD cut-offs in men with PSA4.0-10.0and10.1-20.0ng/ml were also evaluated. Total efficiency in the diagnosis of prostate cancer for different PSA and TZPSAD cut-offs was calculated using the following formula:total efficiency=sensitivity x specificity. The cut-off of the greatest efficiency on the ROC curve was considered as best cut-off for diagnosis of prostate cancer. Student-t test was used to compare the differences of age, PSA, TZV, and TZPSAD between prostate cancer and non-prostate cancer group. Chi square test was used to compare the detection rate of prostate cancer between PSA4.0-10.0and10.1-20.0ng/ml group. Statistical analyses were performed using SPSS program (version17.0, Chicago, IL). All statistical tests were two-sided with a P<0.05considered statistically significant.(3) A total of4211men had their initial PSA measurement at age≤50years old from January2001to November2009were retrospectively retrieved from our hospital. Of these men,11had undergone prostatic biopsy and5were diagnosed with prostate cancer. Those with a diagnosis of prostate cancer were excluded. This left4206men were included in the study. Of these men, PSA velocity was calculated in417who had their PSA measurement twice or more. PSA measurement and prostatic biopsy were performed as Chapter (1). PSA velocity was calculated as the slope of linear regression line of all PSA values collected over time. The important cutoffs of baseline PSA (1.0,2.5and4.0ng/ml) and PSA velocity (0.35,0.75,1.0ng/ml/year) were used to stratify patients in different age groups (≤30,31-39, and40-50years old). The differences of baseline PSA and PSA velocity and the correlation of baseline PSA and PSA velocity were assessed. The distributions of baseline PSA and PSA velocity in men age≤50years old were demonstrated. The correlations between initial PSA, initial PSA age, and PSA velocity were also estimated. Kaplan-meier and log-rank test were used to estimate the significant difference at the risk of PSA≥2.5ng/ml after initial PSA measurement, stratified by median initial PSA (0.6ng/ml).(4) A total of699men who had undergone TRUS guided prostate biopsy between November1999and June2011were retrieved from our hospital. Within this cohort,593(84.8%) underwent13-core biopsy,40(5.7%) underwent6-core biopsy and66(9.4%) underwent4-15core biopsy (not6or13cores). Two hundreds and sixty one men with a PSA of10-50ng/ml underwent a13-core prostate biopsy with complete PV data were included in the study. PV was measured via TRUS. PSA measurement, prostatic biopsy, and PV calculation were performed as Chapter (1). The clinical variables included in analysis were age at prostate biopsy, PSA at time of biopsy, PV, and DRE status. PV was used as both a continuous and categorical variable (stratified by median). Age and PSA were analyzed as a continuous variable and DRE was treated as a categorical variable. Multivariate stepwise Logistic regression was used to determine which variables (PV as a continuous or categoric variable, age and PSA as a continuous variable, and DRE as a categoric variable) were predictive of a positive TRUS biopsy. The rates of prostate cancer among men with different DRE statuses and PSA ranges, stratified by PV medians, were calculated. Statistical analyses were performed using SPSS statistical software (version18.0; SPSS Inc,Chicago, IL). All statistical tests were2-sided with a P<0.05considered to be statistically significant.(5) A total of699men who had undergone trans-rectal ultrasound-guided systematic prostatic biopsy for detecting prostate cancer from November1999to June2011were retrieved from our hospital. Of the699men who had a prostatic biopsy,251had a document of free to total PSA measurements with a biopsy PSA of4.0-20.0ng/ml were included in the study. PSA was analyzed with the following assays:PSA measurement and prostatic biopsy were performed as Chapter (1). f/t PSA was calculated using the following formula:f/t PSA=f PSA (ng/ml)÷t PSA (ng/ml). Receiver operating characteristic (ROC) curve was used to compare the efficiency of PSA and f/t PSA in the diagnosis of prostate cancer in men with a PSA of4.0-10.0and10.1-20.0ng/ml. The efficiencies in the diagnosis of prostate cancer for PSA and f/t PSA best cut-offs in men with PSA4.0-10.0and10.1-20.0ng/ml were also evaluated. Total efficiency in the diagnosis of prostate cancer for PSA and f/t PSA best cut-offs was calculated using the following formula:total efficiency=sensitivity x specificity. The cut-off of the greatest efficiency on the ROC curve was considered as best cut-off for diagnosis of prostate cancer. Student-t test was used to compare the differences of age, PSA, PV, and F/T PSA between prostate cancer and non-prostate cancer group. Chi square test was used to compare the detection rate of prostate cancer between PSA4.0-10.0and10.1-20.0ng/ml group. Statistical analyses were performed using SPSS program (version17.0, Chicago, IL). All statistical tests were two-sided with a P<0.05considered statistically significant.
RESULT (1) Of the535subjects included in the study,41.7%(223/535) had a positive initial prostate biopsy. The median and mean diagnostic PSA levels in our study cohort were18.6and91.4ng/ml, respectively. The median PSA level in men with a positive initial prostate biopsy was statistically higher than those with a negative biopsy (43.4Vs.13.1ng/ml, P<0.001, Mann-Whitney U test). In a multivariate analysis, only age, PV, LogPSA, and DRE were found to be independent predictors of a positive initial prostate biopsy.The logistic regression model yielded the equation below:
Positive initial prostate biopsy probability equation for Chinese population=
e-1.163+0.033Age+1.032DRE-2.821LogePV+2.292LogPSA
1+e-1.163+0.033Age+1.032DRE-2.821LogPV+2.292LogPSA
Using the information from multivariate regression analysis, a nomogram model was developed that allows the calculation of an individual patient's risk for a positive initial prostate biopsy. A concordance index of0.848, representing predictive accuracy, was found upon internal validation of the nomogram.Our nomogram was superior in predictive accuracy to that with diagnostic PSA data, increasing the area under the curve (AUC) from79.7%to84.8%.(2) Of the189men included in the study,78and111had a PSA of4.0-10.Ong/ml and10.1-20.0ng/ml, respectively. A total of40patients (21.2%) were diagnosed with prostate cancer. In78men with a PSA of4.0-10.0ng/ml,16(20.5%) were diagnosed with prostate cancer. In111men with a PSA of10.1-20.0ng/ml,24(21.6%) were diagnosed with prostate cancer. The rate of prostate cancer between men with a PSA of4.0-10.0and10.1-20.0ng/ml groups was not statistically different (P=0.854). The differences of age, prostate transition zone volume between prostate cancer and non-prostate cancer groups were both not statistically significant different (P=0.680and0.293, respectively). The TZPSAD and rate of positive digital rectal examination between prostate cancer and non-prostate cancer groups were both statistically different (P=0.004and0.026, respectively). The areas under the ROC curve (AUCs) for PSA and TZPSAD as continuous variables in predicting prostate cancer in men with a PSA of4.0-10.0ng/ml were0.569and0.702, respectively. When the best PSA cut-off of7.0ng/ml was chosen to predict prostate cancer, the total efficiency was30.8%and corresponding specificity and sensitivity were56.2%and54.8%, respectively. For the best TZPSAD cut-off of0.370ng/ml/ml, the total efficiency was49.9%and the corresponding specificity and sensitivity were68.8%and72.6%, respectively. If PSA7.0ng/ml was chosen for the biopsy cut-off,56.2%(9/16) of the prostate cancer could be diagnosed and the positive biopsy rate was24.3%(9/37). However, if TZPSAD0.370ng/ml/ml was chosen for the biopsy cut-off,68.8%(11/16) of the prostate cancer could be diagnosed and the positive rate of prostate biopsy was up to39.3%(11/28). At least9men could avoid unnecessary prostate biopsy. The AUCs for PSA and TZPSAD as continuous variables in predicting prostate cancer in men with a PSA of10.1-20.0ng/ml were0.463and0.730, respectively. When the best PSA cut-off of13.3ng/ml was chosen to predict prostate cancer, the total efficiency was23.7%and corresponding specificity and sensitivity were66.7%and35.6%, respectively. For the best TZPSAD cut-off of0.500ng/ml/ml, the total efficiency was49.6%and the corresponding specificity and sensitivity were70.8%and70.1%, respectively. If PSA13.3ng/ml was chosen for the biopsy cut-off,66.7%(16/24) of the prostate cancer could be diagnosed and the positive biopsy rate was21.9%(16/73). But, if TZPSAD0.500ng/ml/ml was chosen for the biopsy cut-off,70.8%(17/24) of the prostate cancer could be diagnosed and the positive rate of prostate biopsy was up to39.7%(17/43). At least30men could avoid unnecessary prostate biopsy.(3) A total of4206men without prostate cancer were included. The median initial PSA value in these men was0.6ng/ml. Of these men,1026(24.4%),177(4.2%), and90(2.1%) had a initial PSA of≥1.0≥2.5, and≥4.0ng/ml, respectively. A total of417men had their PSA measurement twice or more. The median PSA velocity in these men was0.03ng/ml/year. Of these men,25(6.0%),13(3.1%), and8(1.9%) had a PSA velocity of≥0.35、≥0.75、≥2.00ng-ml/year,respectively. These were no direct correlations between initial PSA age and initial PSA, initial PSA age and PSA velocity, and initial PSA and PSA velocity (correlation coefficient r=0.077,-0.011and-0.008, respectively; P=0.115,0.831,and0.875, respectively). After a follow-up of up to7.1years from baseline PSA measurement, the risk of PSA≥2.5ng/ml, stratified by median initial PSA (0.6ng/ml) was significantly different (log-rank test, P<0.001).(4) Of the261subjects included in the study,95(36.4%) were diagnosed with prostate cancer. The median and mean PVs in our study cohort were60and68ml, respectively. Median and mean diagnostic PSA in our study cohort were19.3and22.3ng/ml, respectively. The median age, PSA, PV, and rate of positive DRE in men diagnosed with prostate cancer were all statistically significantly higher than those did not have prostate cancer (all p values<0.05). On univariate analysis, the risk of prostate cancer was inversely associated with PV. On stepwise multivariate analysis, PV (as either a continuous or categorical variable), age, PSA, and DRE status were all found to be independent predictors of prostate cancer. Men with a PV of≥60ml (median) were found to be at a decreased risk of having prostate cancer with odds ratios of0.23when compared to those with a PV of <60ml (p value<0.010). The rates of prostate cancer in men with a PV of<60and≥60ml in the PSA of10-19.9ng/ml group were40.6%and15.1%, respectively, while rates for those with a PSA of20-50ng/ml were65.1%and26.8%, respectively. The rates of prostate cancer in for men with a PV of<60or≥60ml and with a positive DRE were71.9%and35.3%, respectively, while the rates for those with a negative DRE saw rates of41.9%and16.7%, respectively.(5) Of the251men included in the study,101and140had a PSA of4.0-10.0ng/ml and10.1-20.0ng/ml, respectively. A total of58patients (23.1%) were diagnosed with prostate cancer. In101men with a PSA of4.0-10.0ng/ml,18(17.8%) were diagnosed with prostate cancer. In140men with a PSA of10.1-20.0ng/ml,40(26.7%) were diagnosed with prostate cancer. The rate of prostate cancer between men with a PSA of4.0-10.0and10.1-20.0ng/ml groups was not statistically different (P=0.103). The differences of f/t PSA and prostate volume between prostate cancer and non-prostate cancer groups were both statistically significant different (all P values<0.05). The PSA between prostate cancer and non-prostate cancer groups were both not statistically different (P=0.361and0.435,respectively).The rates of prostate cancer inversely decreased with f/t PSA increased. Prostate cancer detection rates in men with f/t PSA<10%in PSA4.0-10.0and10.1-20.0ng/ml ranges were46.7%and40.0%, respectively. Whereas, prostate cancer detection rates in men with f/t PSA>25%in PSA4.0-10.0and10.1-20.0ng/ml ranges were only11.1%and11.8%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of4.0-10.0ng/ml were0.569and0.305, respectively. When the best PSA cut-off of8.2ng/ml was chosen to predict prostate cancer, the total efficiency was33.2%and corresponding sensitivity and specificity were50.0%and66.3%, respectively. For the best f/t PSA cut-off of18%, the total efficiency was15.4%and the corresponding sensitivity and specificity were27.8%and55.4%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of10.1-20.0ng/ml were0.458and0.358, respectively. When the best PSA cut-off of15.5ng/ml was chosen to predict prostate cancer, the total efficiency was23.3%and corresponding sensitivity and specificity were40.0%and58.2%, respectively. For the best f/t PSA cut-off of12%, the total efficiency was19.1%and the corresponding sensitivity and specificity were52.5%and36.4%, respectively. The AUCs for PSA and f/t PSA as continuous variables in predicting prostate cancer in men with a PSA of4.0-20.0ng/ml were0.553and0.325, respectively. When the best PSA cut-off of10.5ng/ml was chosen to predict prostate cancer, the total efficiency was29.9%and corresponding sensitivity and specificity were62.1%and48.2%, respectively. For the best f/t PSA cut-off of12%, the total efficiency was15.0%and the corresponding sensitivity and specificity were53.4%and28.0%, respectively. In men with PSA4.0-10.0and10.1-20.0ng/ml, the efficiencies of best cutoffs for f/t PSA were not better than best cutoffs for PSA in diagnosis of prostate cancer.
CONCLUSION (1) Our results indicate that the risk of a positive initial prostate biopsy can be predicted to a satisfactory level in a Chinese population using our nomogram. The nomogram can be used to identify and counsel patients who should consider a prostate biopsy, ultimately enhancing accuracy in diagnosing prostate cancer.(2) Using TZPSAD can improve the efficiency of PSA in diagnosis of prostate cancer and decreases the unnecessary prostatic biopsy in men with a PSA of both 4.0-10.0and10.1-20.0ng/ml.(3) The median baseline PSA and PSA velocity in men younger than50years old with prostate cancer are0.6ng/ml and0.03ng/ml/year, respectively. Men younger than50years old without prostate cancer with an initial PSA higher than median (0.6ng/ml) have a subsequently higher risk of PSA value≥2.5ng/ml.(4) PV is an independent predictor of prostate cancer in men with a PSA of10-50ng/ml. In clinical practice, especially for those countries with lower PCa incidence, PV should be taken into account so as to improve the prostate cancer detection rate and avoid unnecessary biopsy.(5) f/t PSA does not improve the efficiency of prostate specific antigen in diagnosis of prostate cancer in Chinese men with PSA4.0-10.0and10.1-20.0ng/ml.
引文
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