单纯前列腺上皮内瘤回顾性分析(附142例病例分析)

目的通过对前列腺上皮内瘤(PIN)临床资料分析,探讨PIN的生物特性及应对策略。方法对31例无前列腺癌PIN(NPCaPIN)改变患者(其中1级23例,2、3级8例)的临床资料(包括患者血清PSA、fPSA/tPSA、PSA密度等区域计数资料以及穿刺标本免疫组织化学染色结果)进行回顾性分析,以同期确诊为前列腺癌(PCa)、良性前列腺增生(BPH)患者资料作为对照,分析低级别PIN(LGPIN)和高级别PIN(HGPIN)改变之间及NPCaPIN临床特征与PCa、BPH患者临床特征的差异。结果LGPIN和HGPIN改变的患者之间血清PSA水平和年龄存在差异(P<0.05);LGPIN和PCa患者之间血清PSA水平、前列腺体积、fPSA存在显著差异(P<0.01),PSA密度、fPSA/tPSA比值存在差异(P<0.05),和BPH患者之间各项均无明显差异;HGPIN改变和PCa患者之间前列腺体积、fPSA水平和年龄存在差异(P<0.05),和BPH患者之间血清PSA水平差异显著(P<0.01),fPSA/tPSA比值和年龄(P<0.05)存在差异;NPCaPIN和PCa患者之间血清前列腺体积、fPSA水平和年龄、血清PSA水平、PSA密度存在显著差异(P<0.01),和BPH患者之间fPSA/tPSA比值(P<0.05)存在差异。P63、AE1、AE3、P504S、PSA免疫组织化学结果NPCaPIN组类似于BPH而完全异于PCa。结论LGPIN的临床和病理特征与BPH相似,而HGPIN的临床和病理方面具有一定的前列腺恶性肿瘤特征,需要积极的临床追踪观察。     

Extent and zonal distribution of prostatic intraepithelial neoplasia in patients with prostatic carcinoma in Japan: analysis of whole-mounted prostatectomy specimens

BACKGROUND: Prostatic intraepithelial neoplasia (PIN), an intraluminar proliferation of epithelial cells in ducts and acini, is divided into high-grade (HGPIN) and low-grade (LGPIN), based on morphologies. HGPIN is considered to be a putative precursor of prostatic adenocarcinoma (PCA). Information on PIN has been limited in Japan, because PIN had not been regarded as a precursor lesion for PCA. METHODS: In this study, extent and zonal distribution of PIN together with its relationship with PCA were examined in totally embedded radical prostatectomy specimens obtained from 70 patients with PCA. Fifty-three patients received androgen deprivation therapy (castrated) and remaining 17 did not (noncastrated). RESULTS: Frequency of HGPIN in noncastrated cases (76%) was much higher than that in castrated cases (26%) (P < 0.001). LGPIN showed the same tendency, but the difference was smaller. Difference in mean number of HGPIN in noncastrated and castrated cases (12.0 and 6.4, respectively) was more marked than in LGPIN (6.4 and 5.1, respectively). Reduction rate of mean size in HGPIN (26%) by the androgen deprivation therapy was larger than in LGPIN. When evaluated in noncastrated cases, the coexistence of PCA and HGPIN was found in 76% of cases in the nontransition and 53% in the transition zone. Close association of PCA and PIN (相似文献   

The association of prostate stem cell antigen (PSCA) mRNA expression and subsequent prostate cancer risk in men with benign prostatic hyperplasia following transurethral resection of the prostate

BACKGROUND: Prior data showed prostate stem cell antigen (PSCA) mRNA expression in benign prostatic hyperplasia (BPH) tissues. The purpose of the present investigation was to determine whether PSCA mRNA expression in resected BPH samples was associated with the subsequent presence of cancer following transurethral resection of the prostate (TURP). METHODS: PSCA in situ hybridization was performed on the TURP-resected tissues from 288 patients, who were histopathologically confirmed BPH without cancer. All these patients were continuously followed for 9-70 months postoperatively. Univariate and multivariate cox regression analyses were used to evaluate the predictive performance of PSCA mRNA for subsequent cancer onset following TURP. RESULTS: PSCA mRNA was detected in 93/288 (32.3%) of the resected BPH specimens, with a mean positive-labeling cells of 23.8%, in which 22 patients (23.7%) were identified as having PCa on follow-up. Of 195 patients with negative expression for PSCA mRNA 2 (1.0%) were subsequently found with PCa. PSCA mRNA expression levels were directly proportional to higher Gleason score and clinical T stage. Univariate and multivariate cox regression analyses demonstrated that only PSCA mRNA expression was predictive of the subsequent cancer development after TURP, however, PSA velocity was an univariately significant but not multivariately significant predictor. CONCLUSIONS: This prospective study identifies PSCA mRNA in BPH as a significant predictor of cancer development after TURP, suggesting that PSCA may be used to identify patients who are at high risk for subsequent cancer onset following TURP for BPH and the PSCA test may be useful when applied for repeat biopsies.     

HGPIN患者血清PSA特征及首次穿刺活检HGPIN阳性针数对再次活检PCa检出率的影响

目的 探讨高级别前列腺上皮内瘤(high grade prostatic intraepithelial neoplasia,HGPIN)患者血清前列腺特异性抗原(prostate specific antigen,PSA)特征及首次穿刺活检HGPIN阳性针数对再次活检前列腺癌(PCa)检测率的影响.方法 选取2013年2月至2015年12月在本院行前列腺穿刺的患者共320例,均行直肠超声引导下前列腺穿刺活检,分析各类患者血清PSA差异,对结果为非PCa患者于6个月后再次穿刺活检.结果 320例患者首次穿刺活检病理结果显示:其中HGPIN患者80例(孤立型51例,多灶型29例),低级别前列腺上皮内瘤(LGPIN)患者45例,前列腺增生(BPH)患者128例,PCa患者67例;其中PCa患者血清PSA为35.20(13.01,60.55) ng/mL,明显高于BPH、LGPIN、孤立型和多灶型HGPIN患者(P＜0.05);多灶型HGPIN血清PSA为12.15(6.82,16.43) ng/mL,明显高于BPH、LGPIN、孤立型HGPIN患者(P＜0.05);BPH、LGPIN、孤立型HGPIN患者血清PSA比较差异无统计学意义(P＞0.05);多灶性HGPIN患者再次穿刺为PCa的比例为38.46％ (10/26),明显高于BPH、LGPIN和孤立型HG-PIN患者(P＜0.05);BPH、LGPIN和孤立型HGPIN再次穿刺为PCa的比例比较差异无统计学意义(P＞0.05).结论 多灶型HGPIN血清PSA水平高于孤立型HGPIN、BPH以及LGPIN,但低于PCa;多灶型HGPIN患者再次活检PCa的检出率显著高于其他患者.     

Correlation of increased apoptosis and proliferation with development of prostatic intraepithelial neoplasia (PIN) in ventral prostate of the Noble rat

BACKGROUND: Imbalance between cell proliferation and cell apoptosis has been considered a key factor in carcinogenesis. Prostatic intraepithelial neoplasia (PIN) is the most likely precancereous lesion and represents the major target for chemoprevention of prostate cancer. The proliferative and apoptotic activities involved in the development of PIN remain to be elucidated. METHODS: Ventral prostates were removed from Noble rats that were treated with a combination of testosterone (T) and estradiol (E(2)) for certain periods of time, and processed for histopathological grading. To evaluate the relationship between cell proliferation and apoptosis, immunohistochemistry for proliferating cell nuclear antigen (PCNA), Ki-67, and in situ DNA nick labeling (TUNEL) for identifying apoptotic cells, were performed on paraffin sections from prostate samples with PIN lesions. The results were correlated with expression patterns of Bcl-2 and Bax, two proteins related to cell survival and cell apoptosis. RESULTS: Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) were observed in ducts or alveoli after 3 and 5 months of T + E(2) treatment, respectively. Quantitative evaluation of Ki-67 showed an increased proliferative activity in HGPIN. In contrast to normal prostatic ducts and alveoli, which showed no positive staining for Ki-67 in the nuclei of luminal cells, 25% Ki-67-positive cells were detected in luminal cells of HGPIN. Only 7.5% Ki-67-positive cells were found belonging to the basal cell type. The Ki-67 index showed a higher growth rate from normal to HGPIN. The PCNA results showed a similar expression pattern to that of Ki-67 in normal prostate, LGPIN, and HGPIN. Apoptotic index (number of apoptotic cells/total number of cell counted) was significantly higher (P = 0.028) in HGPIN (3.23%) than in control prostate (1.19%). In contrast to control prostate, which showed no definite expression of Bcl-2, an intense positive expression of Bcl-2 in HGPIN was observed. Positive expression of Bax protein was observed in glandular epithelial cells of normal control prostate and HGPIN as well. CONCLUSIONS: Overexpression of Bcl-2 and higher Ki-67 or PCNA indices in HGPIN suggest that abnormal growth of premalignant lesions might result from an increase in cell proliferation. An increased apoptotic rate in HGPIN further implicates that active apoptosis may accelerate cell turnover in the development of premalignant lesions of the prostate.     

Structural changes and alteration in expression of TGF-beta1 and its receptors in prostatic intraepithelial neoplasia (PIN) in the ventral prostate of noble rats

BACKGROUND: Prostatic intraepithelial neoplasia (PIN) is the most likely pre-cancereous lesion and represents the major target for chemoprevention of prostate cancer. The multi-functional role of TGF-beta1, together with its receptors, in normal prostate and development of prostatic neoplasia remains controversial and requires further investigation. METHODS: Ventral prostates were removed from Noble rats treated with a combination of testosterone (T) and estradiol (E(2)) for various periods of time, and processed for ultrastructural examination and histopathological grading. To evaluate the role of TGF-beta1 and TGFbeta receptor types I and II in normal prostate and high-grade PIN development, expression pattern of TGF-beta1 and TGFbeta-RI and TGFbeta-RII were studied on prostate samples with PIN lesions. RESULTS: Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) were observed in ducts or alveoli after three and five months of T + E(2) treatment, respectively. EM study revealed that HGPIN cells were characterized by a reduction in abundance of secretory apparatus and the nucleus with highly irregular and undulated membrane and often with inclusion bodies although the basal lamina remained largely normal. This was associated with a high level of expression of TGF-beta1 in stromal tissue subjacent to foci of HGPIN. No definite positive reactivity of TGF-beta1 was identified in glandular epithelial cells of HGPIN. These results implicated that the major site for the TGF-beta1 production remained to be restricted to stromal compartment at the stage of HGPIN, and a paracrine regulation of TGF-beta1 might be involved in the development of HGPIN. Positive staining for the TGFbeta-RI was found in the cytoplasm of luminal epithelial cells of normal ventral prostate. The intense positive reactivity for TGFbeta-RI was also identified in prostates with HGPIN lesions. Similar expression pattern of TGFbeta-RII was also observed. CONCLUSIONS: Based on the EM study, we concluded that HGPIN in ventral prostate was accompanied with alterations in nuclear morphology together with a change in secretory activity. The over expression of TGFbeta-RI and RII in HGPIN cells as well as TGF-beta1 in stromal tissue subjacent to HGPIN implicated a growth-stimulating role instead of inhibiting role of this peptide growth factor during the early stage of prostatic neoplasia.     

Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry

ObjectiveTo identify the differences of 5-methylcytosine (5-MC) level between primary prostate cancer tissues (PCTs), prostate cancer-adjacent benign tissues (PCABTs), low-grade prostatic intraepithelial neoplasia (LGPIN), and high-grade prostatic intraepithelial neoplasia (HGPIN), and further analysis the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis.Materials and methodsImmunohistochemistry method with a 5-MC monoclonal antibody was used to identify the 5-methylcytosine (5-MC) levels in PCTs, PCABTs, LGPIN, and HGPIN specimens in the present study. Statistical analysis with SPSS software (SPSS Inc., Chicago, IL) was used to compare differences of 5-MC levels in the four groups and evaluate the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis.ResultsWe found that 38 of 48 (79.1%) patients studied showed a decrease in 5-MC staining of PCTs compared with PCABTs. The difference in the methylation levels for the PCTs and the PCABTs was highly statistically significant (P < 0.001). Spearman correlation showed there was no statistically significant association between the average score of 5-MC staining and Gleason score sum. Kaplan-Meier survival analysis showed that patient group with no or weak 5-MC staining compared with group with moderate and strong 5-MC staining was associated with better survival of patients, although there was no statistically significant difference between the 2 groups in predicating prognosis (P = 0.385). The average scores of 5-MC staining for LGPIN, HGPIN, PCABTs, and PCTs groups were 6.91, 1.58, 6.63, and 3.10, respectively. The methylation level of HGPIN group, as well as that of PCTs group, was significantly lower than those of LGPIN (P < 0.001; P < 0.001) and PCABTs groups (P < 0.001; P < 0.001), respectively, with the 5-MC levels of PCABTS group similar to that of LGPIN group (P = 0.476). 5-MC levels of HGPIN group was lower than that PCTs group (P = 0.004).ConclusionsWe found that global DNA methylation was low in most prostate cancer compared with benign regions from the same patient's sections. None of the DNA hypomethylation changes in primary cancers were associated with pathologic grade and clinical prognosis. In addition, immunohistochemistry showed that the global methylation was lower in HGPIN compared with LGPIN and methylcytosine staining in HGPIN was lower than that of PCTs. The results suggest that global DNA hypomethylation might play an important role in the process of prostate cancer initiation rather than progression.     

前列腺干细胞抗原在人前列腺癌组织中的表达及意义

目的　探讨前列腺干细胞抗原 (PSCA)在国人前列腺癌 (PCa)组织中表达的临床意义。　方法　采用免疫组织化学 (IHC)和核酸原位杂交 (ISH)方法检测 4 0例PCa、2 0例良性前列腺增生(BPH)和 2 0例前列腺上皮内瘤 (PIN)组织标本PSCA蛋白和mRNA表达 ,半定量法计算PSCA阳性表达细胞百分数和阳性表达强度 ,比较各组织间表达水平的差异及其与PCa分级、临床分期之间的关系。　结果　PCa、BPH、PIN组织PSCA中度阳性到强阳性表达分别为 85 % (34/ 4 0 )、2 0 % (4/ 2 0 )和35 % (7/ 2 0 ) ;PCa组织PSCA表达水平与BPH和PIN比较差异有统计学意义 (P <0 .0 5 ) ,BPH与PIN比较差异无统计学意义 (P >0 .0 5 ) ;PCa组织PSCA表达水平随Gleason评分及临床分期增加而升高。　结论　人PCa组织有PSCA蛋白质和mRNA的过表达 ,且与PCa病理分级、临床分期呈正相关 ,可能对PCa的诊断及判断预后有潜在价值。     

Epigenetic events, remodelling enzymes and their relationship to chromatin organization in prostatic intraepithelial neoplasia and prostatic adenocarcinoma

OBJECTIVE: To explore the nuclear chromatin phenotype, overall epigenetic mechanisms, chromatin remodelling enzymes and their role as diagnostic biomarkers in prostate lesions, using high-resolution computerized quantitative digital image analysis (DIA). MATERIALS AND METHODS: A tissue microarray (TMA) was constructed using paraffin wax-embedded prostatic tissues from 78 patients, containing 30 cores of benign prostatic hyperplasia (BPH), 10 of low-grade prostatic intraepithelial neoplasia (LGPIN), 38 of prostate adenocarcinoma, 20 of BPH tissue excised at 0.6-1 mm from LGPIN lesions, and 10 of BPH prostatic tissues obtained 0.6-1 mm from high-grade PIN (HGPIN) lesions. Chromatin phenotype was assessed on haematoxylin-stained sections using high-resolution texture analysis. For quantitative immunohistochemistry, antibodies raised against acetylated histone H3 lysine 9 (AcH3K9), 5'methylcytidine (5MeC) and the chromatin remodelling ATPase ISWI (SNF2H and SNF2L) were used. The immunodensity was measured using DIA to determine the epigenetic profile of the cases. At least 60 nuclei were measured from each case. RESULTS: There were many statistically significant differences in staining intensity and nuclear distribution patterns in chromatin phenotype and immunostaining (p 相似文献   

Lesions predictive for prostate cancer in a screened population: first and second screening round findings

BACKGROUND: We evaluated the incidence of prostate cancer, high-grade prostatic intraepithelial neoplasia (PIN) and lesions suspicious for prostate cancer (LSPC) in sextant biopsies in two subsequent screening rounds at a 4-year interval and their predictive value for subsequent prostate cancer detection. METHODS: In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), 4,117 men underwent sextant biopsy in the 1st screening round. The 2nd round was performed at a 4-year interval and biopsies were taken in 1,840 men. RESULTS: The incidences of prostate cancer, LSPC and PIN in the 1st, respectively 2nd round were 24.6, resp. 19.9% (P = 0.001), 2.7, resp. 2.8% and 0.8, resp. 2.5% (P < 0.0001). Prostate cancer incidence after repeat biopsy for LSPC in the 1st, respectively 2nd round was 36.7 and 17.0%, and after repeat biopsy for PIN 13.3% in both rounds, respectively. Men with a benign biopsy in the 1st round had a significantly lower prostate cancer incidence in the 2nd round compared to men who did not undergo biopsy in the 1st round (10.7 vs. 22.7%, P < 0.0001). CONCLUSIONS: The decrease of prostate cancer detection in the 2nd round was associated with an increase in the incidence of PIN. Strikingly, LSPC diagnosed during the 1st round, but not during the 2nd round were predictive for prostate cancer, while isolated PIN was never predictive for prostate cancer. PIN should not be an indication for repeat biopsy in a screening population. Importantly a 1st round benign biopsy outcome proved to be a negative predictor of subsequent prostate cancer detection.     

Complete androgen ablation suppresses prostate stem cell antigen (PSCA) mRNA expression in human prostate carcinoma

BACKGROUND: Prostate stem cell antigen (PSCA) is a recently identified glycosylphosphatidylinositol (GPI)-anchored cell surface protein belonging to the Thy-1/Ly-6 family of cell surface antigens. Prior data in prostate cancers indicated that PSCA is directly regulated by androgens and PSCA expression increases with high-tumor grade, advanced stage, extracapsular invasion, and androgen-independent progression. The effect of complete androgen ablation (CAA) on tumor PSCA mRNA expression has not been elucidated. The purpose of the present study was to investigate the variations in the expression levels of PSCA mRNA before and after CAA, and further evaluate the clinically prognostic value of PSCA in human prostate carcinoma. MATERIALS AND METHODS: PSCA in situ hybridization (ISH) was performed on the cancerous pretreatment biopsy or transurethral resection of prostate (TURP) tissue of 42 men with primarily organ-confined prostate cancer before CAA, and on their tumor tissue from radical retropubic prostatectomy after CAA with bicalutamide and goserelin acetate for 3 months prior to undergoing radical prostatectomy. Tumor cytoplasmic staining of PSCA mRNA was evaluated by two independent pathologists and the differences of PSCA mRNA expression levels between the samples before and after CAA were analyzed using the Student's t-test. Thirty-six to forty months follow-up studies after radical retropubic prostatectomy were performed and aimed at assessing the correlation of PSCA mRNA expression level with local recurrences or metastases from the cancer. RESULTS: The percent of cells positive for PSCA mRNA by ISH labeling declined from 67.3% (0-89%)+/-9.4% before CAA to 33.8% (0-92%)+/-7.7% after CAA (P<0.001). Before CAA, 40 of 42 cases (95.2%) were positive for PSCA mRNA labeling, however, after CAA the percentage of positive reactivity of PSCA mRNA was decreased to 27 of 40 cases (67.5%), in which none was found with local recurrences or distant metastases after radical prostatectomy on follow-up. This decline in PSCA mRNA labeling was dependent on the original tumor grade with Gleason score of or=8: 73.4%+/-13.8% (P<0.05, respectively). The rest 13 cases had the increased percentage of cells positive for PSCA mRNA after CAA, in which 3 cases were found with local recurrences and 4 cases with distant metastases from tumor on follow-up. CONCLUSIONS: Our data demonstrate that CAA for prostate cancer can suppress PSCA mRNA expression with a tumor grade dependence and the increased expression of PSCA mRNA after CAA may be a clinically adverse predictor for tumor recurrences or distant metastases.     

Apolipoprotein-D: a novel cellular marker for HGPIN and prostate cancer

BACKGROUND: High grade prostatic intraepithelial neoplasia (HGPIN) is a putative pre-malignant lesion of the prostate. While apolipoprotein-D (Apo-D), an androgen-regulated hydrophobic transporter protein, is expressed in prostate tumors, its expression in HGPIN is unknown. METHODS: Immunoreactivity for Apo-D and another androgen-regulated protein, prostate specific antigen (PSA), was investigated in 64 radical prostatectomy tissues by video image analysis. RESULTS: Eighty two percent of prostatectomy specimens demonstrated moderate to strong Apo-D immunoreactivity in areas of HGPIN. In comparison, weak Apo-D immunoreactivity was observed in non-malignant areas in only 24% of specimens. The median (range) percentage cellular area of HGPIN immunopositive for Apo-D (9.7%, 0-42.9), and the cellular concentration of Apo-D (MIOD 3.1, 0-13.3), were intermediate between that of normal (area 0%, 0-53.5%, MIOD 0, 0-12.6) and early stage prostate cancer tissues (area 29.2%, 0-90.8%, MIOD 6.7, 0-28.1). This increase in Apo-D expression from non-malignant, through HGPIN to prostate cancer was statistically significant (P < 0.001), and contrasted with the decrease observed in PSA staining between adjacent areas of normal glands, HGPIN, and cancer (P = 0.026). CONCLUSIONS: The presence of high levels of immunoreactive Apo-D in HGPIN and prostate cancer, but not in non-malignant epithelial cells, is consistent with HGPIN being an intermediate lesion in the transition to prostate cancer, and suggests that cellular Apo-D expression is a marker of malignant transformation of the prostate.     

前列腺上皮内瘤诊治分析(附13例报告)

目的　探讨前列腺上皮内瘤 (PIN)的临床特征、诊断和处理。　方法　分析 13例PIN患者的临床资料。良性前列腺增生合并PIN 4例 (HGPIN 1例 ,LGPIN 3例 ) ,行TURP手术 3例 ,耻骨上经膀胱前列腺摘除术 1例 ;前列腺癌并发PIN 8例 (均为HGPIN) ,行前列腺根治性切除术 5例 ,TURP手术 3例 ;体检发现LGPIN 1例 ,因血PSA持续升高 ,TURP术后给予雄激素全阻断治疗。　结果　 13例均经病理确诊 ,血PSA检测、直肠指诊和经直肠B超等检查对PIN诊断无意义。 4例BPH合并PIN患者均健康存活 (3～ 5年 ) ,1例 1年后随访活检发现进展为前列腺癌 ,行前列腺根治性切除术 ;5例前列腺癌并发PIN患者随访 2～ 5年后健康存活 ,1例死于其它疾病 ,2例失访 ;体检发现者 3个月后血PSA明显下降。　结论　病理检查是诊断PIN的惟一方法。对PIN应进行雄激素全阻断治疗并密切随访 ,定期穿刺活检是早期发现PIN恶变的有效方法。     

The proportion of cores with high-grade prostatic intraepithelial neoplasia on extended-pattern needle biopsy is significantly associated with prostate cancer on site-directed repeat biopsy

OBJECTIVE: To determine whether the predictive value of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) for an unsampled prostate cancer on an extended biopsy is lower due to more thorough prostate sampling, and whether the proportion of cores with HGPIN is associated with prostate cancer, as isolated HGPIN on sextant prostate biopsy is associated with a 27-57% risk of prostate cancer on repeat biopsy. PATIENTS AND METHODS: All extended prostate biopsies taken by one urologist over 6 years were reviewed for patients with isolated HGPIN on initial biopsy. Biopsies were evaluated for histological features and the proportion of cores with HGPIN. The clinical characteristics and pathological findings from subsequent biopsies were determined. RESULTS: Of 577 men having extended biopsies, 48 had isolated HGPIN, followed by one to four site-directed repeat biopsies. Although only 10 (21%) had cancer on the first repeat biopsy, overall 15 (31%) had cancer. Those with cancer on repeat biopsy had a significantly higher proportion of cores with HGPIN, i.e. 29% vs 15%, cancer vs no cancer, respectively (P = 0.04). CONCLUSIONS: Isolated HGPIN on extended biopsy conferred a 31% risk of unsampled prostate cancer. The proportion of cores with HGPIN on initial biopsy was significantly associated with the risk of cancer. The same was not true for age, race, prostate-specific antigen level, or the findings on digital rectal examination. The significant association between the proportion of cores with HGPIN and the risk of cancer suggests that patients with unifocal HGPIN on extended biopsy be managed expectantly, whereas those with multifocal HGPIN be re-biopsied.     

Prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance

The aim of the present paper was to review the morphological spectrum of prostatic intraepithelial neoplasia (PIN), its relationship to carcinoma of the prostate (PCa) and its clinical significance. We reviewed the literature on premalignant lesions of the prostate, with an emphasis on high grade prostatic intraepithelial neoplasia (HGPIN). HGPIN is the most likely precursor of PCa, according to almost all available evidence. HGPIN is characterized by cellular proliferations within pre-existing ducts and acini, with nuclear and nucleolar enlargement similar to PCa. The clinical importance of recognizing HGPIN is based on its association with PCa. In recent years, a significant decline from 36% to 22% in the predictive value of cancer after an initial diagnosis of HGPIN. A major factor contributing to the decreased incidence of cancer after a diagnosis of HGPIN on needle biopsy in the contemporary era is related to increased needle biopsy core sampling, which detects many associated cancers on initial biopsy. Some recent studies have suggested that molecular findings associated with HGPIN might be able to predict which men are more likely to have cancer on re-biopsy.     

核干因子在前列腺癌中的表达及其临床意义

目的:探讨核干因子(NS)基因在前列腺癌组织中的表达及其临床意义。方法:利用RT-PCR及免疫组化方法对前列腺癌、良性前列腺增生(BPH)及高级别前列腺上皮内瘤(HGPIN)组织中NS基因的表达进行检测,并探讨NS蛋白表达水平与前列腺癌患者临床指标的关系。结果:前列腺癌中NSmRNA表达水平显著高于BPH中的表达水平,NS蛋白在前列腺癌中的强阳性、阳性及弱阳性表达率分别为48.8%、36.6%及12.2%,在BPH中分别为4.0%、32.0%及56.0%,在HGPIN中分别为5.0%、25.0%及60.0%,在前列腺癌中的表达水平显著高于BPH及HGPIN中的水平,具有统计学意义(P<0.05)。NS基因表达水平与前列腺癌的分化程度呈负相关,细胞分化程度越差,NS基因表达水平越高。结论:前列腺癌中高表达NS基因,NS基因在前列腺癌的不良分化和恶性增殖中可能起着重要作用。     

External beam radiotherapy (EBRT) suppressed prostate stem cell antigen (PSCA) mRNA expression in clinically localized prostate cancer

BACKGROUND: Prostate stem cell antigen (PSCA), a recently identified glycosylphosphatidylinositol (GPI)-anchored cell surface protein belonging to the Thy-1/Ly-6 family of cell surface antigens, is overexpressed in human prostate cancer (PCa). Our recent data indicated that complete androgen ablation could significantly suppress PSCA mRNA expression in primarily organ-confined PCa. The effect of external beam radiotherapy (EBRT), one of the curative treatment options for localized PCa, on tumor PSCA mRNA expression has not been elucidated. The purpose of the present study was to investigate the variations in the expression levels of PSCA mRNA before and after EBRT, and further evaluate the prognostic value of PSCA in this disease. MATERIALS AND METHODS: Between January 1999 and June 2005, 87 men with clinically localized adenocarcinoma of the prostate received only EBRT with a total dose of 65-70 Gy for 6.5-7 weeks. PSCA in situ hybridization (ISH) was performed on the cancerous pretreatment biopsy or transurethral resection of prostate (TURP) tissue and post-treatment biopsy tissue of all 87 men, respectively. Tumor cytoplasmic staining of PSCA mRNA was evaluated by two independent pathologists and the differences of PSCA mRNA expression levels between the samples before and after EBRT were analyzed using the Student's t-test. Twenty-four to seventy months continuous follow-up studies after treatment were performed and aimed at assessing the correlation of PSCA mRNA expression level with biochemical relapse and/or distant metastases from the cancer. RESULTS: The percent of cells positive for PSCA mRNA by ISH labeling declined from 71.2% (0-93%) +/- 9.7% before EBRT to 30.7% (0-90%) +/- 5.3% after EBRT (P<0.001). Before EBRT, 81 of 87 cases (93.1%) were positive for PSCA mRNA labeling, however, after EBRT the percentage of positive reactivity of PSCA mRNA was decreased to 62 of 81 cases (76.5%), in which 59 men (95.2%) were found without biochemical relapse or distant metastases on follow-up. This decline in PSCA mRNA labeling was directly proportional to higher pretreatment serum PSA level, higher tumor grade (Gleason score), and higher clinical T stage. The rest 19 cases had the increased percentage of cells positive for PSCA mRNA after EBRT, in which 15 cases developed biochemical relapse and/or distant metastases from tumor on follow-up. CONCLUSIONS: We found that EBRT for PCa can significantly suppress PSCA mRNA expression and the elevated PSCA mRNA level after EBRT may be a clinically adverse predictor for tumor progression.     

Alpha-methylacyl-CoA racemase (AMACR) expression in normal prostatic glands and high-grade prostatic intraepithelial neoplasia (HGPIN): association with diagnosis of prostate cancer

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR) is strongly expressed in prostate cancer with variable expression in high-grade prostatic intraepithelial neoplasia (HGPIN) and low expression in normal prostate. We examined whether AMACR expression in HGPIN and normal tissue was associated with subsequent diagnosis of cancer or proximity to a cancer focus. METHODS: Needle core biopsies from 45 patients with isolated HGPIN, 12 radical prostatectomy (RP) specimens with prostatic carcinoma and 6 cystoprostatectomies without prostatic carcinoma were immunostained for AMACR. Among patients with HGPIN, 23 (cases) showed cancer on a later biopsy and 22 (controls) had no cancer with at least 3 consecutive negative biopsies. RESULTS: In the biopsy set, the mean AMACR expression per gland in the normal compartment of the cases (0.29) was significantly higher than the controls (0.21) (P = 0.0006). In the RP set, normal glands near a cancer focus had higher mean AMACR expression than those that were distant (P = 0.0006). There was no difference within the HGPIN compartment between cases and controls in the biopsies, or between near and distant glands in the RP set. Mean AMACR staining of normal glands in the cystoprostatectomy specimens was significantly lower than in normal glands in close proximity to a cancer focus. CONCLUSIONS: Higher expression of AMACR in normal glands near a focus of cancer, as well as in the subjects eventually showing cancer, suggests a possible field effect in prostatic carcinogenesis. AMACR expression in normal glands therefore might be a useful predictor for repeat biopsy outcomes or as an intermediate endpoint in chemoprevention studies.     

Overexpression of cyclooxygenase-2 in human prostate carcinoma and prostatic intraepithelial neoplasia-association with increased expression of Polo-like kinase-1

BACKGROUND: Cyclooxygenases (COX) as well as Polo-like kinases (PLK) are involved in proliferation and cell cycle regulation and have been suggested for preventive and therapeutic approaches in prostate carcinoma. METHODS: In this study, we studied expression and prognostic impact of COX-2 in invasive prostate carcinoma, prostatic intraepithelial neoplasia (PIN), atrophic glands, and normal prostatic glands, and investigated the association between COX-2 and PLK-1. RESULTS: We observed a positivity for COX-2 in 72.1% of PIN and in 44.7% of prostate carcinomas with an overexpression of COX-2 in prostate cancer and PIN compared to benign prostatic tissue (P < 0.0005). Furthermore, we observed a strong correlation between expression of PLK-1 and COX-2 (P < 0.0005). CONCLUSIONS: To our knowledge, this is the first report of a correlation between COX-2 and PLK-1 in a malignant tumor. COX-2 and PLK-1 may be interesting targets for new molecular therapies in prostate cancer.     

Do all patients with high‐grade prostatic intraepithelial neoplasia on initial prostatic biopsy eventually progress to clinical prostate cancer?

OBJECTIVE: To assess the clinical outcome of patients with a diagnosis of high-grade prostatic intraepithelial neoplasia (PIN) on initial prostatic biopsy, with a minimum of 5 years of follow-up, as such patients are at greater risk of having prostate cancer on subsequent biopsy. PATIENTS AND METHODS: Between November 1992 and October 1998, 21 patients were identified as having PIN on their initial transrectal ultrasonography-guided prostate biopsy. None of these patients had a focus of cancer on the initial biopsy. Their medical data were reviewed retrospectively to determine the natural history of PIN in these patients. Patients who were not identified as having cancer were followed every 6-12 months with prostate-specific antigen (PSA) testing and digital rectal examinations (DRE). RESULTS: A mean (range) of 7 (2-8) cores were taken at initial biopsy; the mean age of the patients was 63 (53-77) years and mean PSA level 9.1 (4.9-17.6) ng/mL. Six patients had an abnormal DRE at presentation. A mean of 8 (7-10) cores were obtained on the second biopsy; six patients were diagnosed with cancer, with a mean Gleason score of 6 (5-7), while three were diagnosed with persistent PIN. These three patients had a third prostate biopsy which showed cancer of Gleason score 6 in one and benign prostatic hyperplasia in two. After a mean follow-up of 72.2 (60-84) months, none of the remaining 12 patients was diagnosed with clinically significant cancer. Five of these patients went on to a third prostate biopsy, with no evidence of cancer. One patient died from unrelated causes during this period. CONCLUSION: This study affirms our current practice of following patients with PIN conservatively if a second or third subsequent prostate biopsy is negative. Whether PIN is a premalignant lesion or merely a lesion associated with cancer needs to be addressed in multicentre studies with a follow-up of > 10 years.