ERG相关融合基因在前列腺癌早期诊断和淋巴结转移预测中的应用及局部晚期前列腺癌的外科治疗
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摘要
目的与背景：
前列腺癌是西方国家发病率最高的泌尿系恶性肿瘤，其死亡率高居第二位，仅次于肺癌。我国前列腺癌发病率相对较低，但随着近年来国人饮食结构和生活习惯的改变，前列腺癌发病率在我国呈逐年升高的趋势。数据显示我国上海地区2009年前列腺癌的发病率为25.88%/10万，标准化发病率已达11.37/10万。由此可见前列腺癌已逐渐成为威胁我国男性人口健康的一重大疾患。
前列腺癌的最终诊断必须依靠前列腺穿刺活检。课题组前期研究回顾性分析了近10年在我中心接受12针前列腺穿刺活检且PSA值为4-20ng/L的923例患者临床病理资料。结果显示总体前列腺癌检出率为27.4%，有18.3%的患者诊断为高级别前列腺上皮内瘤（Highgrade prostatic intraepithelial neoplasia，HGPIN），3.5%为前列腺上皮非典型增生，其余50.8%为良性前列腺增生。前列腺穿刺所取得的组织量很少，加之常规影像学检查手段往往无法对肿瘤进行准确定位，使我们无法对这些仅有的少量细胞或腺体进行准确诊断和分析。尤其是早期灶性癌变和HGPIN的鉴别十分困难。HGPIN被认为是前列腺癌的癌前病变。然而，首次诊断为HGPIN的患者在重复穿刺活检时也只有约20-40%诊断为前列腺癌，提示并非所有HGPIN都需要马上接受重复穿刺。如何将这些需要即刻重复穿刺的患者鉴别出来是目前一大诊疗难点。研究表明，大部分恶性肿瘤在形态学尚未有异常表现时其分子生物学指标已有显著异常表现。因此，研究重点已逐渐转向分子病理领域。Tomlins等发现TMPRSS2-ERG相关融合基因是前列腺癌特异性分子标志物，它存在于前列腺癌和部分HGPIN病灶中。课题组前期研究用荧光原位杂交方法（Fluorescence in situ hybridization，FISH）方法检测前列腺癌组织和非癌组织中ERG相关融合基因畸变率，应用ROC曲线方法建立了ERG相关融合基因诊断前列腺癌的最佳诊断阈值（1.6%），其敏感性和特异性均大于90.0%。本研究拟用FISH检测首次穿刺诊断为HGPIN的162例患者的穿刺组织中ERG相关融合基因畸变率，根据我课题组前期所建立的诊断阈值将首次穿刺诊断为HGPIN的患者分成两组，对这组患者进行密切随访和必要的重复穿刺活检，比较这两组患者最终前列腺癌检出率的差异。以求对这组患者的重复穿刺策略的制定提供一些新依据
淋巴结转移是前列腺癌的首要预后影响因素，术前准确评估是否存在淋巴结转移对于临床决策意义重大。遗憾的是，目前仍无敏感性和特异性俱佳的检测方法来准确反映前列腺癌淋巴结转移的存在。临床常用核磁共振（MRI）、计算机断层扫描（CT）检测前列腺癌盆腔淋巴结转移，其敏感性不足40%。一些包括了PSA、穿刺Gleason评分和临床分期等临床指标的预测模型预测前列腺癌盆腔淋巴结转移的敏感性和特异性也仅有70.0%左右。鉴于上述方法的局限性，分子生物学手段逐渐成为研究重点。近期有研究显示，在多中心、多病灶发生的前列腺癌中只有ERG相关融合基因阳性的结节才具备转移能力。提示ERG相关融合基因可用来帮助我们诊断和预测前列腺癌早期盆腔淋巴结转移。本研究拟分析在华南地区5家三甲医院接受前列腺癌根治+盆腔扩大淋巴结清扫术的143例患者的穿刺组织中ERG相关融合基因畸变率，通过ROC曲线建立诊断前列腺癌淋巴结转移的最佳阈值。分析这一阈值的敏感性和特异性，为术前准确进行淋巴结分期提供新手段。
临床局限性前列腺癌手术后可能诊断为T3-T4进展期前列腺癌。按既往理念，这部分患者是不适合接受根治性手术的。放疗联合内分泌治疗或者单纯保守性内分泌治疗才是治疗这组患者的主要手段。最近，一些研究表明根治性手术治疗局部晚期前列腺癌的疗效和放疗相当，甚至优于单纯内分泌治疗；切除前列腺癌原发病灶后可增加术后辅助性内分泌治疗的效果，同时延迟其进展为全身转移性前列腺癌。这使得大家开始重新讨论用根治性前列腺切除治疗局部晚期前列腺癌。本研究拟回顾性分析在我中心接受腹腔镜下前列腺癌根治术联合盆腔扩大淋巴结清扫术的152例患者临床病理资料，分析其近期功能恢复情况和远期肿瘤控制情况。以求为局部晚期前列腺癌的外科治疗提供一些的临床实践经验。
材料与方法：
1.从2008.5至2010.5课题组收集了华南地区5家三甲医院首次穿刺诊断为HGPIN的前列腺穿刺标本，选取具有代表性的一条组织检测ERG相关融合基因畸变率。根据课题组前期研究所检测的诊断前列腺癌的最佳阈值（1.6%），将患者分为ERG相关融合基因阳性（≥1.6%）组和ERG相关融合基因阴性组（<1.6%）。所有患者在首次穿刺后3-6个月内均进行一次重复穿刺，以后以PSA速率为主要观察指标联合DRE检查结果对患者进行重复穿刺。比较两组患者后续前列腺癌检出率的差异。
2.选取在华南地区5家三甲医院行前列腺根治性切除+盆腔扩大淋巴结清扫术的143例患者，复习其穿刺病理结果，选取最具代表性的一条组织检测ERG相关融合基因畸变率。以术后淋巴结状态作为阳性事件进行分析，在ROC曲线下建立用ERG相关融合基因预测前列腺癌盆腔淋巴结转移的最佳阈值，分析这一阈值的敏感性和特异性，阳性预测值和阴性预测值。
3.回顾性分析我中心2004年1月到2011年7月152例术后诊断病理为局部晚期前列腺癌（T3-4N0-1M0）患者临床病理资料。详细记录手术情况、控尿及并发症资料。并用生存曲线分析该组病例的3年和5年无生化复发生存率、无临床进展生存率、总体生存率、肿瘤特异性生存率。
结果：
1.自2008年5月到2010年5月，课题组收集了162例首次穿刺诊断为HGPIN的患者，重复穿刺或者经尿道前列腺电切术后病理显示61例患者诊断为前列腺癌（37.7%），其中ERG相关融合基因阳性的59例患者中56例（94.9%，包括15例首次重复穿刺时发现和41例随访过程中发现的前列腺癌）被诊断为前列腺癌；而ERG相关融合基因阴性的102例患者中仅有5例（4.9%；包括4例首次重复穿刺发现和1例为随访中发现的前列腺癌）诊断为前列腺癌。ERG相关融合基因阳性HGPIN后续诊断为前列腺癌的风险明显高于ERG相关融合基因阴性的患者（P<0.001）。
2.接受盆腔淋巴结清扫的143例前列腺癌患者中，56例淋巴结阳性，87例淋巴结阴性。淋巴结转移性前列腺癌患者的ERG相关融合基因畸变率明显高于淋巴结阴性的前列腺癌患者ERG相关融合基因畸变率（P<0.001）。ROC曲线分析显示，ERG相关融合基因预测早期前列腺癌患者发生淋巴结转移的最佳阈值为2.6%。该阈值的敏感性为80.4%（95%CI：67.6-89.8），特异性为85.1%（95%CI：75.8-91.8）；其阳性预测值和阴性预测值分别为0.776（95%CI：0.668-0.853）和0.871（95%CI：0.791-0.923）。
3.自2004年1月至2011年7月，在中山大学附属第三医院泌尿外科接受腹腔镜下前列腺癌根治+盆腔扩大淋巴结清扫术患者共152例，其中位随访时间为48个月（13-87个月）。术后6个月和12个月控尿率达91.4％和94.7%。随访过程中，80例发生生化复发，3年和5年无生化复发生存率分别为59.2％和47.3％；多因素分析显示，Gleason评分(HR:1.66,95%CI:1.05-2.64, P=0.031)，病理分期(HR:1.64,95%CI:1.2-2.23, P=0.002)及切缘阳性(HR:1.75,95%CI:1.04-2.95, P=0.035)是术后生化复发的独立危险因素。19例患者死亡，9例死于肿瘤，3年和5年总体生存率分别为90.2％和86.0％；3年和5年肿瘤特异性生存率分别为95.8％和92.8％。淋巴结阳性患者和淋巴结阴性患者术后无生化复发生存率(42.6%vs49.5%,P=0.491)，总体生存率(83.4%vs87.3%P=0.503)及肿瘤特异性生存率(92.3%vs94.9%, P=0.801)无明显统计学差异。
结论：
1． ER相关融合基因阳性HGPIN后续前列腺癌的检出率很高，对于ERG相关融合基阳性HGPIN可进行靶向重复穿刺或直接进行前列腺癌相关治疗； ERG相关融合基因阴性HGPIN后续前列腺癌检出率很低，无需进行即刻重复活检，可等待观察。
2． ERG相关融合基因诊断前列腺癌盆腔淋巴结转移的最佳阈值为2.6%，这一阈值诊断前列腺癌盆腔淋巴结转移兼具高敏感性和特异性，为前列腺癌淋巴结清扫及后续辅助治疗提供了新的可靠依据。
3．腹腔镜下前列腺癌根治术+盆腔扩大淋巴结清扫治疗局部晚期前列腺癌疗效肯定，是这组患者安全有效的治疗手段。
Background and Objective:
Prostate cancer is the most common urological malignancy in Western countries, which wasthe second leading cause of death following lung cancer. The incidence of prostate cancer isrelatively low in China. But with the changes of diet structure and living habits since the lastdecade, the incidence of prostate cancer is increasing in our country. In2009, the incidence ofprostate cancer in Shanghai was about25.88/100,000. It indicates that prostate cancer hasgradually become one of the major diseases that threaten the health of our male population.
The final diagnosis of prostate cancer must rely on the prostate biopsy. Our previous studyanalyzed the clinical and pathological data of923cases with serum PSA level of4-20ng/ml whounderwent12needle prostate biopsy schemes in the past10years. The results showed that overallcancer detection rate was27.4%. There were18.3%,3.5%and50.8%were diagnosed ashigh-grade prostatic intraepithelial neoplasia (HGPIN), Atypical small acinar proliferation ofprostate (ASAP) and benigen prostatic hyperplasia (BPH), respectively.
Small amount of prostate tissue is collected during needle biopsy. And the conventionalimaging methods can not accurately locate the tumor lesions. So we can not precisely analyze anddiagnose a small amount of tumor cells mixed with a large number of normal cells or glands.Especially, it is hardly to distinguish early focal prostate cancer and the HGPIN. There are about20%patients who received prostate needle biopsy for elevated serum PSA level dignozed asHGPIN. HGPIN is considered to be precancerous lesions of the prostate cancer. However, onlyabout20-40%of those diagnosed as PIN at initial biopsy are diagnosed as prostate cancer insubsequent repeat biopsy. These data indicates that not all patients with HGPIN are required toaccept re-biopsy urgently. Several researches demonstrate that biochemical and molecularabnormalities appear prior to the changes of morphology features for many malignant tumors.They suggest that molecular pathology methods can be used as a supplementary measure toidentify these early cancers.Tomlins and colleagues found that TMPRSS2-ERG rearrangementwas a prostate cancer-specific molecular marker. We intend to detect ERG rearrangement ratesusing fluorescence in situ hybridization (FISH) in biopsy samples which were diagnosed asHGPIN at initial biopsy. Patients were divided into two groups according to the cut-off (1.6%)established in our previous research using receiver operating characteristic curve (ROC). All theenrolled HGPIN patients received one repeat biopsy within3-6months after initial biopsy. Andthen, re-biopsy was done on the base of PSA velocity. Cancer detecting rates were compared inthese two groups of HGPIN patients.
Lymph node metastasis is a leading prognositic factor for prostate cancer. However, it is verydifficult to accurately assess lymph node metastasis of prostate cancer before surgery. Magneticresonance image (MRI) and computed tomography (CT) were the most common used modality todetect lymph node metastases in recent clinical practice, but its sensitivity is less than40%. Somenomograms involved serum PSA level, biopsy Gleason score and clinical T stage have beenintroduced to predict lymph node metastasis of prostate cancer in recent years. The sensitivity andspecificity of these models are also only about70.0%. Thus, some robust methods with highsensitivity and specificity are urgently needed to deal with this clinical challenge. Recent studiesdemonstrate that only those with positive ERG rearrangement prostate cancer locus had potentialability to form a metastatic lesion. It indicated that TMPRSS2-ERG might be employed to predictlymph node metastasis of prostate cancer. In current study, we plan to evaluate ERG rearrangement rates in patients underwent prostatectomy and pelvic lymph node dissection.Optimal cut-off for predicting lymph node metastasis of prostate cancer is established using ROCcurve. We aim to introduce a new method for predicting lymph node metastasis of prostate cancer.
Clinical localized prostate cancer might be upstaged as T3-T4advanced prostate cancer aftersurgery. According to the previous concept, these patients are not suitable for radical surgery.Radiotherapy combined with hormonal therapy or conservative endocrine therapy alone is thestandard treatment strategy for this subgroup of patients. Recently, a number of studies haveshown the efficacy of radical surgery for the treatment of locally advanced prostate cancer. And itsefficacy is as well as radiotherapy, and even better than endocrine therapy alone. In addition,remove of the primary prostate cancer focus can increase the response of adjuvant endocrinetherapy, systemic metastatic can be delayed. Consequently, we begin to re-discuss the radicalsurgery for locally advanced prostate cancer. This study retrospectively analyzes the clinical andpathological characteristics of152patients with pathological advanced prostate cancer whounderwent laparoscopic radical prostatectomy in our center. Function recovery and long-termtumor control results are recorded and analyzed. We aim to provide further clinical practice of thesurgical treatment of this group of patients.
Materials and Methods:
1、On the basis of the cut-off value established previously, the162patients with HGPIN werestratified to two groups: one group with positive ERG rearrangement and the other with negativeERG rearrangement. Subsequent prostate cancer detecting rates between the two groups werecompared.
2、One hundred and forty-three biopsy samples from whom underwent prostatectomy andpelvic lymph node dissection were collected. ERG-rearrangement rate was evaluated using FISH.The optimal cut-off of ERG rearrangement for predicting lymph node metastasis was establishedusing receiver operating characteristic curve (ROC). And the sensitivity and specificity of thiscut-off were calculated.
3、From January2004to July2011,152cases including105locally advanced PCa and47lymph node metastatic PCa who treated by LRP with extended lymph node dissection (ePLND)were included in this study. Operation records, complications and urinary continence rates werepresented. Oncologic outcomes expressed as3-and5-yr biochemical recurrence-free, overall andcancer-specific survival rates were analyzed using Kaplan-Meier survival curve.
Results:
1. Of the162HGPIN patients,59HGPIN with positive ERG rearrangement and103with negative ERG rearrangement were observed. A total of56of59(94.9%) HGPIN cases withpositive ERG rearrangement and5of103(4.9%) HGPIN cases with negative ERG rearrangementwere diagnosed with prostate cancer during repeat biopsy or transurotheral resection of prostate(TURP). The rates of subsequent detection of prostate caner between the two groups werestatistical different (p<0.001).
2. Of the143patients who underwent prostatectomy and pelvic lymph node dissection in ourinstitute from January2004to July2011,56patients had positive lymph node and87cases hadnegative lymph node. There were significant differences in rearrangement rates of ERGrearrangement between lymph node-positive and-negative prostate cancer (P <0.001). Theoptimal cutoff value to predict lymph node metastasis by ERG rearrangement was established,being2.6%with a sensitivity at80.4%[95%CI:67.6–89.8] and a specificity at85.1%(95%CI:75.8–91.8). The positive predicting value and negative predicting value were0.776（95%CI：0.668-0.853） and0.871（95%CI：0.791-0.923）, respectively。
3. The mean operation time and bleeding were240minutes and110ml, respectively. After12-87months (median48months) of follow-up,91.4%and94.7%of the patients were urinarycontinence at6and12months, respectively.80biochemical recurrent diseases were detected. The3-and5-yr biochemical progression-free survival rates were59.2%and47.3%, respectively.Multivariate analysis showed that Gleason score (HR:1.66,95%CI:1.05-2.64, P=0.031),pathological stage (HR:1.64,95%CI:1.2-2.23, P=0.002) and surgical margin (HR:1.75,95%CI:1.04-2.95, P=0.035) were independent risk factors for subsequent biochemical relapse. The3-and5-yr overall and cancer-specific survival rates were90.2%,86.0%and95.8%,92.3%, respectively.There were no significant differences in biochemical recurrence-free (42.6%vs49.5%, P=0.491),overall (83.4%vs87.3%P=0.503) and cancer-specific survival rates (92.3%vs94.9%, P=0.801)between lymph node positive and negative PCa.
Conclusion:
1、HGPIN patients with positive ERG rearrangement had significant higher rate for subsequentdiagnosis of prostate cancer in re-biopsy than those with negative ERG rearrangement. Forpatients with positive ERG rearrangement, prostate cancer related therapy can be adapted forrather high incidence of prostate cancer detection rate, while those with negative ERGrearrangement HGPIN, the probability of detecting prostate cancer is low enough to omit rebiopsy.
2、ERG rearrangement with the optimal cut-off of2.6%with both high sensitivity and specificitycan accurately predict lymph node metastasis of prostate cancer. PLND can be conductedaccording to this promising biomarker.
3、LRP plus ePLND is feasible to cases with locally advanced non-extra node metastatic PCa.
前列腺癌是西方国家发病率最高的泌尿系恶性肿瘤，其死亡率高居第二位，仅次于肺癌。我国前列腺癌发病率相对较低，但随着近年来国人饮食结构和生活习惯的改变，前列腺癌发病率在我国呈逐年升高的趋势。数据显示我国上海地区2009年前列腺癌的发病率为25.88%/10万，标准化发病率已达11.37/10万。由此可见前列腺癌已逐渐成为威胁我国男性人口健康的一重大疾患。
前列腺癌的最终诊断必须依靠前列腺穿刺活检。课题组前期研究回顾性分析了近10年在我中心接受12针前列腺穿刺活检且PSA值为4-20ng/L的923例患者临床病理资料。结果显示总体前列腺癌检出率为27.4%，有18.3%的患者诊断为高级别前列腺上皮内瘤（Highgrade prostatic intraepithelial neoplasia，HGPIN），3.5%为前列腺上皮非典型增生，其余50.8%为良性前列腺增生。前列腺穿刺所取得的组织量很少，加之常规影像学检查手段往往无法对肿瘤进行准确定位，使我们无法对这些仅有的少量细胞或腺体进行准确诊断和分析。尤其是早期灶性癌变和HGPIN的鉴别十分困难。HGPIN被认为是前列腺癌的癌前病变。然而，首次诊断为HGPIN的患者在重复穿刺活检时也只有约20-40%诊断为前列腺癌，提示并非所有HGPIN都需要马上接受重复穿刺。如何将这些需要即刻重复穿刺的患者鉴别出来是目前一大诊疗难点。研究表明，大部分恶性肿瘤在形态学尚未有异常表现时其分子生物学指标已有显著异常表现。因此，研究重点已逐渐转向分子病理领域。Tomlins等发现TMPRSS2-ERG相关融合基因是前列腺癌特异性分子标志物，它存在于前列腺癌和部分HGPIN病灶中。课题组前期研究用荧光原位杂交方法（Fluorescence in situ hybridization，FISH）方法检测前列腺癌组织和非癌组织中ERG相关融合基因畸变率，应用ROC曲线方法建立了ERG相关融合基因诊断前列腺癌的最佳诊断阈值（1.6%），其敏感性和特异性均大于90.0%。本研究拟用FISH检测首次穿刺诊断为HGPIN的162例患者的穿刺组织中ERG相关融合基因畸变率，根据我课题组前期所建立的诊断阈值将首次穿刺诊断为HGPIN的患者分成两组，对这组患者进行密切随访和必要的重复穿刺活检，比较这两组患者最终前列腺癌检出率的差异。以求对这组患者的重复穿刺策略的制定提供一些新依据
淋巴结转移是前列腺癌的首要预后影响因素，术前准确评估是否存在淋巴结转移对于临床决策意义重大。遗憾的是，目前仍无敏感性和特异性俱佳的检测方法来准确反映前列腺癌淋巴结转移的存在。临床常用核磁共振（MRI）、计算机断层扫描（CT）检测前列腺癌盆腔淋巴结转移，其敏感性不足40%。一些包括了PSA、穿刺Gleason评分和临床分期等临床指标的预测模型预测前列腺癌盆腔淋巴结转移的敏感性和特异性也仅有70.0%左右。鉴于上述方法的局限性，分子生物学手段逐渐成为研究重点。近期有研究显示，在多中心、多病灶发生的前列腺癌中只有ERG相关融合基因阳性的结节才具备转移能力。提示ERG相关融合基因可用来帮助我们诊断和预测前列腺癌早期盆腔淋巴结转移。本研究拟分析在华南地区5家三甲医院接受前列腺癌根治+盆腔扩大淋巴结清扫术的143例患者的穿刺组织中ERG相关融合基因畸变率，通过ROC曲线建立诊断前列腺癌淋巴结转移的最佳阈值。分析这一阈值的敏感性和特异性，为术前准确进行淋巴结分期提供新手段。
临床局限性前列腺癌手术后可能诊断为T3-T4进展期前列腺癌。按既往理念，这部分患者是不适合接受根治性手术的。放疗联合内分泌治疗或者单纯保守性内分泌治疗才是治疗这组患者的主要手段。最近，一些研究表明根治性手术治疗局部晚期前列腺癌的疗效和放疗相当，甚至优于单纯内分泌治疗；切除前列腺癌原发病灶后可增加术后辅助性内分泌治疗的效果，同时延迟其进展为全身转移性前列腺癌。这使得大家开始重新讨论用根治性前列腺切除治疗局部晚期前列腺癌。本研究拟回顾性分析在我中心接受腹腔镜下前列腺癌根治术联合盆腔扩大淋巴结清扫术的152例患者临床病理资料，分析其近期功能恢复情况和远期肿瘤控制情况。以求为局部晚期前列腺癌的外科治疗提供一些的临床实践经验。
材料与方法：
1.从2008.5至2010.5课题组收集了华南地区5家三甲医院首次穿刺诊断为HGPIN的前列腺穿刺标本，选取具有代表性的一条组织检测ERG相关融合基因畸变率。根据课题组前期研究所检测的诊断前列腺癌的最佳阈值（1.6%），将患者分为ERG相关融合基因阳性（≥1.6%）组和ERG相关融合基因阴性组（<1.6%）。所有患者在首次穿刺后3-6个月内均进行一次重复穿刺，以后以PSA速率为主要观察指标联合DRE检查结果对患者进行重复穿刺。比较两组患者后续前列腺癌检出率的差异。
2.选取在华南地区5家三甲医院行前列腺根治性切除+盆腔扩大淋巴结清扫术的143例患者，复习其穿刺病理结果，选取最具代表性的一条组织检测ERG相关融合基因畸变率。以术后淋巴结状态作为阳性事件进行分析，在ROC曲线下建立用ERG相关融合基因预测前列腺癌盆腔淋巴结转移的最佳阈值，分析这一阈值的敏感性和特异性，阳性预测值和阴性预测值。
3.回顾性分析我中心2004年1月到2011年7月152例术后诊断病理为局部晚期前列腺癌（T3-4N0-1M0）患者临床病理资料。详细记录手术情况、控尿及并发症资料。并用生存曲线分析该组病例的3年和5年无生化复发生存率、无临床进展生存率、总体生存率、肿瘤特异性生存率。
结果：
1.自2008年5月到2010年5月，课题组收集了162例首次穿刺诊断为HGPIN的患者，重复穿刺或者经尿道前列腺电切术后病理显示61例患者诊断为前列腺癌（37.7%），其中ERG相关融合基因阳性的59例患者中56例（94.9%，包括15例首次重复穿刺时发现和41例随访过程中发现的前列腺癌）被诊断为前列腺癌；而ERG相关融合基因阴性的102例患者中仅有5例（4.9%；包括4例首次重复穿刺发现和1例为随访中发现的前列腺癌）诊断为前列腺癌。ERG相关融合基因阳性HGPIN后续诊断为前列腺癌的风险明显高于ERG相关融合基因阴性的患者（P<0.001）。
2.接受盆腔淋巴结清扫的143例前列腺癌患者中，56例淋巴结阳性，87例淋巴结阴性。淋巴结转移性前列腺癌患者的ERG相关融合基因畸变率明显高于淋巴结阴性的前列腺癌患者ERG相关融合基因畸变率（P<0.001）。ROC曲线分析显示，ERG相关融合基因预测早期前列腺癌患者发生淋巴结转移的最佳阈值为2.6%。该阈值的敏感性为80.4%（95%CI：67.6-89.8），特异性为85.1%（95%CI：75.8-91.8）；其阳性预测值和阴性预测值分别为0.776（95%CI：0.668-0.853）和0.871（95%CI：0.791-0.923）。
3.自2004年1月至2011年7月，在中山大学附属第三医院泌尿外科接受腹腔镜下前列腺癌根治+盆腔扩大淋巴结清扫术患者共152例，其中位随访时间为48个月（13-87个月）。术后6个月和12个月控尿率达91.4％和94.7%。随访过程中，80例发生生化复发，3年和5年无生化复发生存率分别为59.2％和47.3％；多因素分析显示，Gleason评分(HR:1.66,95%CI:1.05-2.64, P=0.031)，病理分期(HR:1.64,95%CI:1.2-2.23, P=0.002)及切缘阳性(HR:1.75,95%CI:1.04-2.95, P=0.035)是术后生化复发的独立危险因素。19例患者死亡，9例死于肿瘤，3年和5年总体生存率分别为90.2％和86.0％；3年和5年肿瘤特异性生存率分别为95.8％和92.8％。淋巴结阳性患者和淋巴结阴性患者术后无生化复发生存率(42.6%vs49.5%,P=0.491)，总体生存率(83.4%vs87.3%P=0.503)及肿瘤特异性生存率(92.3%vs94.9%, P=0.801)无明显统计学差异。
结论：
1． ER相关融合基因阳性HGPIN后续前列腺癌的检出率很高，对于ERG相关融合基阳性HGPIN可进行靶向重复穿刺或直接进行前列腺癌相关治疗； ERG相关融合基因阴性HGPIN后续前列腺癌检出率很低，无需进行即刻重复活检，可等待观察。
2． ERG相关融合基因诊断前列腺癌盆腔淋巴结转移的最佳阈值为2.6%，这一阈值诊断前列腺癌盆腔淋巴结转移兼具高敏感性和特异性，为前列腺癌淋巴结清扫及后续辅助治疗提供了新的可靠依据。
3．腹腔镜下前列腺癌根治术+盆腔扩大淋巴结清扫治疗局部晚期前列腺癌疗效肯定，是这组患者安全有效的治疗手段。
Background and Objective:
Prostate cancer is the most common urological malignancy in Western countries, which wasthe second leading cause of death following lung cancer. The incidence of prostate cancer isrelatively low in China. But with the changes of diet structure and living habits since the lastdecade, the incidence of prostate cancer is increasing in our country. In2009, the incidence ofprostate cancer in Shanghai was about25.88/100,000. It indicates that prostate cancer hasgradually become one of the major diseases that threaten the health of our male population.
The final diagnosis of prostate cancer must rely on the prostate biopsy. Our previous studyanalyzed the clinical and pathological data of923cases with serum PSA level of4-20ng/ml whounderwent12needle prostate biopsy schemes in the past10years. The results showed that overallcancer detection rate was27.4%. There were18.3%,3.5%and50.8%were diagnosed ashigh-grade prostatic intraepithelial neoplasia (HGPIN), Atypical small acinar proliferation ofprostate (ASAP) and benigen prostatic hyperplasia (BPH), respectively.
Small amount of prostate tissue is collected during needle biopsy. And the conventionalimaging methods can not accurately locate the tumor lesions. So we can not precisely analyze anddiagnose a small amount of tumor cells mixed with a large number of normal cells or glands.Especially, it is hardly to distinguish early focal prostate cancer and the HGPIN. There are about20%patients who received prostate needle biopsy for elevated serum PSA level dignozed asHGPIN. HGPIN is considered to be precancerous lesions of the prostate cancer. However, onlyabout20-40%of those diagnosed as PIN at initial biopsy are diagnosed as prostate cancer insubsequent repeat biopsy. These data indicates that not all patients with HGPIN are required toaccept re-biopsy urgently. Several researches demonstrate that biochemical and molecularabnormalities appear prior to the changes of morphology features for many malignant tumors.They suggest that molecular pathology methods can be used as a supplementary measure toidentify these early cancers.Tomlins and colleagues found that TMPRSS2-ERG rearrangementwas a prostate cancer-specific molecular marker. We intend to detect ERG rearrangement ratesusing fluorescence in situ hybridization (FISH) in biopsy samples which were diagnosed asHGPIN at initial biopsy. Patients were divided into two groups according to the cut-off (1.6%)established in our previous research using receiver operating characteristic curve (ROC). All theenrolled HGPIN patients received one repeat biopsy within3-6months after initial biopsy. Andthen, re-biopsy was done on the base of PSA velocity. Cancer detecting rates were compared inthese two groups of HGPIN patients.
Lymph node metastasis is a leading prognositic factor for prostate cancer. However, it is verydifficult to accurately assess lymph node metastasis of prostate cancer before surgery. Magneticresonance image (MRI) and computed tomography (CT) were the most common used modality todetect lymph node metastases in recent clinical practice, but its sensitivity is less than40%. Somenomograms involved serum PSA level, biopsy Gleason score and clinical T stage have beenintroduced to predict lymph node metastasis of prostate cancer in recent years. The sensitivity andspecificity of these models are also only about70.0%. Thus, some robust methods with highsensitivity and specificity are urgently needed to deal with this clinical challenge. Recent studiesdemonstrate that only those with positive ERG rearrangement prostate cancer locus had potentialability to form a metastatic lesion. It indicated that TMPRSS2-ERG might be employed to predictlymph node metastasis of prostate cancer. In current study, we plan to evaluate ERG rearrangement rates in patients underwent prostatectomy and pelvic lymph node dissection.Optimal cut-off for predicting lymph node metastasis of prostate cancer is established using ROCcurve. We aim to introduce a new method for predicting lymph node metastasis of prostate cancer.
Clinical localized prostate cancer might be upstaged as T3-T4advanced prostate cancer aftersurgery. According to the previous concept, these patients are not suitable for radical surgery.Radiotherapy combined with hormonal therapy or conservative endocrine therapy alone is thestandard treatment strategy for this subgroup of patients. Recently, a number of studies haveshown the efficacy of radical surgery for the treatment of locally advanced prostate cancer. And itsefficacy is as well as radiotherapy, and even better than endocrine therapy alone. In addition,remove of the primary prostate cancer focus can increase the response of adjuvant endocrinetherapy, systemic metastatic can be delayed. Consequently, we begin to re-discuss the radicalsurgery for locally advanced prostate cancer. This study retrospectively analyzes the clinical andpathological characteristics of152patients with pathological advanced prostate cancer whounderwent laparoscopic radical prostatectomy in our center. Function recovery and long-termtumor control results are recorded and analyzed. We aim to provide further clinical practice of thesurgical treatment of this group of patients.
Materials and Methods:
1、On the basis of the cut-off value established previously, the162patients with HGPIN werestratified to two groups: one group with positive ERG rearrangement and the other with negativeERG rearrangement. Subsequent prostate cancer detecting rates between the two groups werecompared.
2、One hundred and forty-three biopsy samples from whom underwent prostatectomy andpelvic lymph node dissection were collected. ERG-rearrangement rate was evaluated using FISH.The optimal cut-off of ERG rearrangement for predicting lymph node metastasis was establishedusing receiver operating characteristic curve (ROC). And the sensitivity and specificity of thiscut-off were calculated.
3、From January2004to July2011,152cases including105locally advanced PCa and47lymph node metastatic PCa who treated by LRP with extended lymph node dissection (ePLND)were included in this study. Operation records, complications and urinary continence rates werepresented. Oncologic outcomes expressed as3-and5-yr biochemical recurrence-free, overall andcancer-specific survival rates were analyzed using Kaplan-Meier survival curve.
Results:
1. Of the162HGPIN patients,59HGPIN with positive ERG rearrangement and103with negative ERG rearrangement were observed. A total of56of59(94.9%) HGPIN cases withpositive ERG rearrangement and5of103(4.9%) HGPIN cases with negative ERG rearrangementwere diagnosed with prostate cancer during repeat biopsy or transurotheral resection of prostate(TURP). The rates of subsequent detection of prostate caner between the two groups werestatistical different (p<0.001).
2. Of the143patients who underwent prostatectomy and pelvic lymph node dissection in ourinstitute from January2004to July2011,56patients had positive lymph node and87cases hadnegative lymph node. There were significant differences in rearrangement rates of ERGrearrangement between lymph node-positive and-negative prostate cancer (P <0.001). Theoptimal cutoff value to predict lymph node metastasis by ERG rearrangement was established,being2.6%with a sensitivity at80.4%[95%CI:67.6–89.8] and a specificity at85.1%(95%CI:75.8–91.8). The positive predicting value and negative predicting value were0.776（95%CI：0.668-0.853） and0.871（95%CI：0.791-0.923）, respectively。
3. The mean operation time and bleeding were240minutes and110ml, respectively. After12-87months (median48months) of follow-up,91.4%and94.7%of the patients were urinarycontinence at6and12months, respectively.80biochemical recurrent diseases were detected. The3-and5-yr biochemical progression-free survival rates were59.2%and47.3%, respectively.Multivariate analysis showed that Gleason score (HR:1.66,95%CI:1.05-2.64, P=0.031),pathological stage (HR:1.64,95%CI:1.2-2.23, P=0.002) and surgical margin (HR:1.75,95%CI:1.04-2.95, P=0.035) were independent risk factors for subsequent biochemical relapse. The3-and5-yr overall and cancer-specific survival rates were90.2%,86.0%and95.8%,92.3%, respectively.There were no significant differences in biochemical recurrence-free (42.6%vs49.5%, P=0.491),overall (83.4%vs87.3%P=0.503) and cancer-specific survival rates (92.3%vs94.9%, P=0.801)between lymph node positive and negative PCa.
Conclusion:
1、HGPIN patients with positive ERG rearrangement had significant higher rate for subsequentdiagnosis of prostate cancer in re-biopsy than those with negative ERG rearrangement. Forpatients with positive ERG rearrangement, prostate cancer related therapy can be adapted forrather high incidence of prostate cancer detection rate, while those with negative ERGrearrangement HGPIN, the probability of detecting prostate cancer is low enough to omit rebiopsy.
2、ERG rearrangement with the optimal cut-off of2.6%with both high sensitivity and specificitycan accurately predict lymph node metastasis of prostate cancer. PLND can be conductedaccording to this promising biomarker.
3、LRP plus ePLND is feasible to cases with locally advanced non-extra node metastatic PCa.
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