alpha-Methylacyl coenzyme A racemase, Ki-67, and topoisomerase IIalpha in cystoprostatectomies with incidental prostate cancer

alpha-Methylacyl coenzyme A racemase (AMACR), Ki-67, and topoisomerase IIalpha were immunohisto-chemically evaluated in prostate carcinoma (PCa), high-grade prostatic intraepithelial neoplasia (HPIN), normal-looking epithelium (NEp), and atrophy in 20 cystoprostatectomy (CyP) and 20 radical prostatectomy (RP) specimens with pT2a Gleason score 6 PCa. The aim was to see whether there were differences in marker expression between CyP and RP specimens. The results showed that the proportions of AMACR-, Ki-67-, and topoisomerase IIalpha-positive cells in the CyP and RP specimens increased from NEp and atrophy through HPIN, away from and adjacent to PCa, to PCa. AMACR expression in PCa in CyP specimens was slightly lower than in RP specimens, but the differences were not significant; there were significant differences in Ki-67 and topoisomerase IIalpha indices. Our findings in marker expression in NEp, atrophy, and HPIN suggest that there are some differences in the field effects in terms of prostatic carcinogenesis between CyP and RP specimens.     

HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent cancer

Previous studies have demonstrated HER2 protein overexpression and/or gene amplification in a subset of patients with clinically significant prostate cancer (PCa), especially in the androgen-independent phase of the disease. There are no studies on incidentally detected PCa. The aim of the study was to analyze HER2 expression and gene amplification in PCa incidentally detected in cystoprostatectomies. High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. Comparison was made with clinically detected PCa, both untreated and hormonally treated, and with androgen-independent PCa. Nineteen cystoprostatectomy (CyP) and 44 radical prostatectomy specimens (25 untreated and 19 hormonally treated) with pT2a Gleason score 6 cancer and HGPIN were used in this study. It also included 9 specimens of transurethral resection of the prostate with hormone-independent cancer and 8 cases of normal prostate tissue from CyP specimens without PCa and prostatic intraepithelial neoplasia. HER2 protein and Ki-67 were investigated immunohistochemically. Patients with immunohistochemical scores of 2+ and 3+ were considered to have HER2 overexpression (HercepTest method). Dual-color fluorescence in situ hybridization analysis was performed using the CEP-17/HER dual probe combination. High-grade prostatic intraepithelial neoplasia showed HER2 overexpression in 26% of the CyP cases and in 40% and 83% of the untreated and treated cases, respectively. Prostate cancer showed HER2 overexpression in 16% of cases in the CyP group and in 36% and 47.5% in the untreated and treated groups, respectively. HER2 overexpression was present in 78% of androgen-independent cancers. HER2 gene amplification was seen in a small proportion of nuclei and some of the cases. In HGPIN, it ranged from 1.1% (in 5 cases) in the CyP group to 2.1% (in 10 cases) and 1.9% (in 6 cases) in the untreated and treated groups, respectively. In PCa, the proportion of nuclei with gene amplification was 0.7% (in 3 cases) in the CyP group, 2.6% (in 10 cases) and 2.5% (in 12 cases) in the untreated and treated groups, respectively, and 9% (in 6 cases) in the androgen-independent PCa. Ki-67 expression in HGPIN and PCa in CyP specimens was lower than in the radical prostatectomies and cases of transurethral resection of the prostate. Our findings in the current HER2-related study indicate that incidentally detected cancer has features of less aggressiveness than clinically detected cancer. This may contribute to a better understanding of the results obtained in screening programs where insignificant cancers are detected along with clinically significant cancers.     

Co‐expression of TLR‐9 and MMP‐13 is associated with the degree of tumour differentiation in prostate cancer

In vitro experiments demonstrated that stimulation of Toll‐like receptor 9 (TLR‐9) by synthetic TLR‐9 ligands induces the invasion of TLR‐9‐expressing prostate cancer cells through matrix metalloproteinase 13 (MMP‐13). However, the clinical value of TLR‐9 and MMP‐13 co‐expression in the pathophysiology of the prostate is unknown. In the study, we evaluated the expression levels and clinical significance of the TLR‐9 and MMP‐13 in a series of prostate tissues. One hundred and eighty prostate tissues including prostate cancer (PCa) (n = 137), high‐grade prostatic intraepithelial neoplasia (HPIN) (n = 18) and benign prostatic hyperplasia (BPH) (n = 25) were immunostained for the TLR‐9 and MMP‐13 markers. Subsequently, the correlation between the TLR‐9 and MMP‐13 staining scores and clinicopathological parameters was obtained. Higher expressions of TLR‐9 and MMP‐13 were found in PCa and high‐grade prostatic intraepithelial neoplasia compared to benign prostatic hyperplasia tissues. Among PCa samples, a positive relationship was revealed between the MMP‐13 expression and Gleason score (P < 0.001). There was a significant correlation between TLR‐9 expression and regional lymph node involvement (P = 0.04). The expression patterns of TLR‐9 and MMP‐13 markers demonstrated a reciprocal significant correlation between the two markers in the same series of prostate samples (P < 0.001). Furthermore, the Gleason score of TLR‐9^high/MMP‐13^high and TLR‐9^low/MMP‐13^low phenotypes showed a significant difference (P = 0.002). Higher expressions of TLR‐9 and MMP‐13 can confer aggressive behaviour to PCa. Therefore, these markers may be used as a valuable target for tailored therapy of PCa.     

An update on atypical large glandular proliferations of the prostate

The differential diagnosis of prostatic atypical large gland proliferations includes several benign and malignant entities. This review focusses on issues relevant to the practising pathologist, particularly around areas of controversy such as high-grade prostatic intraepithelial neoplasia (HGPIN) and intraductal carcinoma of the prostate (IDCP). HGPIN is a putative precursor of prostate cancer, but its clinical relevance is as a surrogate marker of unsampled prostate cancer, thereby identifying patients who would benefit from a prompt repeat biopsy. The incidence of missed prostate cancer is much lower in contemporary practice due to pre-biopsy MRI and extended sampling protocols so HGPIN is currently less important. It is however important to distinguish HGPIN from PIN-like carcinoma and IDCP. PIN-like carcinoma is considered a histological subtype/variant of acinar prostate carcinoma and should be graded as Gleason pattern 3. A diagnosis of cribriform HGPIN should not be made in needle biopsies as such a proliferation may represent IDCP. This review discusses controversies related to the diagnosis, reporting and management of IDCP. A personalized approach to management of patients with isolated IDCP in needle biopsies that is based on the histological and radiological features of an individual case is outlined.     

Immunohistochemical expression of prostate tumor overexpressed 1 in cystoprostatectomies with incidental and insignificant prostate cancer. Further evidence for field effect in prostatic carcinogenesis

Prostate tumor overexpressed 1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. It has been suggested that overexpression of prostate tumor overexpressed 1 can contribute to the proliferative status of prostate tumor cells and, thus, to their biologic behavior. Prostate tumor overexpressed 1 and Ki-67 were immunohistochemically evaluated in prostate cancer, high-grade prostatic intraepithelial neoplasia, and normal-looking epithelium in 20 cystoprostatectomies and 20 radical prostatectomies with pT2a Gleason score 6 prostate cancer. The aim was to see whether there were differences in marker expression between cystoprostatectomies and radical prostatectomies. The proportions of prostate tumor overexpressed 1– and Ki-67–positive cells in the cystoprostatectomies and radical prostatectomies increased from normal-looking epithelium through high-grade prostatic intraepithelial neoplasia, away from and adjacent to prostate cancer, to prostate cancer. Prostate tumor overexpressed 1 expression in prostate cancer in cystoprostatectomies was lower than in radical prostatectomies, the differences being significant; there were significant differences in Ki-67 indices. In conclusion, our findings related to prostate tumor overexpressed 1 expression in high-grade prostatic intraepithelial neoplasia, evaluated adjacent and away from prostate cancer, and in incidental and clinical cancers give further support to the concept of field effect in prostatic carcinogenesis as well as to differences in the process of prostatic carcinogenesis between cystoprostatectomies and radical prostatectomies.     

前列腺疾病中TK1和Ki-67的表达

目的通过对前列腺癌、前列腺上皮内瘤变、前列腺良性增生及其正常前列腺组织中胸苷激酶1（TK1）和细胞增殖蛋白（MIB-1）标记Ki-67的表达，探讨其对前列腺癌的治疗、预后所起的作用。方法采用免疫组化ABC法检测前列腺癌（PCa）42例，前列腺上皮内瘤变（PIN）35例，良性前列腺增生（BPH）25例和正常前列腺（NP）组织10例中TK1及Ki-67的表达。结果良性前列腺增生及正常前列腺组织中几乎检测不到增殖细胞，在前列腺上皮内瘤中增殖细胞所占的百分比大约为16％～17％，在前列腺癌组织中TK1阳性表达率57．1％，高于Ki-67阳性表达率（47．6％，P〈0．05）。结论TK1不仅同Ki-67一样，可作细胞增殖的指标，还因其参与DNA合成及细胞间“旁观者效应”等原因，从而给临床提供治疗及预后方面有价值的参考。     

High-grade Prostatic Intraepithelial Neoplasia of the Prostate: The Precursor Lesion of Prostate Cancer

High-grade intraepithelial neoplasia (HGPIN) is a lesion which is widely believed to be a precursor of prostatic adenocarcinoma. Correct morphologic identification of HGPIN and an understanding of how this diagnosis affects clinical management in the research setting are necessary as HGPIN is a premalignant lesion with many genetic alterations similar to prostate cancer, but is not yet invasive cancer. As such it is critical to differentiate between benign entities, HGPIN, and prostatic adenocarcinoma for experimental design and data interpretation. This review discusses HGPIN, clarifies the terminology used in pathology reports, and describes the clinical and research implications of this entity.     

前列腺癌中EZH2 mRNA及蛋白表达与细胞增殖的关系

目的 探讨EZH2 mRNA和蛋白在前列腺癌中的表达及其与肿瘤细胞增殖的关系.方法 通过组织芯片技术,应用原位杂交和免疫组化方法检测48例前列腺癌中EZH2 mRNA和蛋白的表达以及Ki-67增殖指数,同时检测15例良性前列腺增生组织(BPH)和12例高级别上皮内瘤变(HGPIN)中EZH2 mRNA和蛋白的表达.结果 前列腺癌组织中EZH2蛋白和mRNA阳性率分别为87.50%和81.25%,均高于BPH和HGPIN,差异有显著性(P<0.05).EZH2蛋白与mRNA表达之间差异无统计学意义(P>0.05).EZH2蛋白的表达与Gleason分级、TNM分期相关(P<0.05),与患者年龄和术前血清前列腺特异抗原(PSA)水平无关(P>0.05).EZH2 mRNA的表达与TNM分期相关(P<0.05),与患者年龄、术前PSA水平及Gleason分级无关(P>0.05).EZH2蛋白表达程度与Ki-67细胞增殖指数呈明显正相关(r=0.746,P<0.05).结论 EZH2 mRNA及其蛋白在前列腺癌中表达上调,通过促进肿瘤细胞增殖使得肿瘤发生、发展,有望成为预测前列腺癌恶性程度进程的参考指标.     

Comparison of monoclonal antibody (P504S) and polyclonal antibody to alpha methylacyl-CoA racemase (AMACR) in the work-up of prostate cancer

AIM: Studies using a monoclonal (P504S) and a polyclonal antibody (p-AMACR) to alpha-methylacyl-CoA racemase (AMACR) have shown variable expression in prostate cancer (PCa). The goal is to compare the sensitivity of both antibodies in PCa and evaluate their utility in the work-up of atypical prostate needle biopsies (NBXs). METHODS AND RESULTS: A tissue microarray (TMA) with 248 samples of benign prostate, high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa samples, 20 NBXs with minute PCa and 32 NBXs with 'atypical' foci were stained with P504S and p-AMACR. Ninety percent of PCa (76/76 TMA, 16/20 NBXs) showed predominantly strong p-AMACR expression while 87% (65/69 TMA, 16/20 NBXs) showed variable P504S expression (sensitivity 90% versus 87%, P = 0.10). In HGPIN, P504S and p-AMACR were positive in 77% and 91% of samples, respectively. In the 'atypical' NBXs group, 53% were classified as PCa, 12% benign and 35% atypical, suspicious for PCa, after review of the basal marker. Of atypical, suspicious for PCa, P504S/p-AMACR helped convert the diagnosis to PCa in 5/11 (45%) cases, where, despite negative basal cell markers, morphology was less than optimal. CONCLUSIONS: Differences between P504S and p-AMACR appear marginal and clinically insignificant. AMACR is negative in a subset of unequivocal minute PCa with both antibodies. However, when utilized in proper context, AMACR may offer significant advantage in converting an 'atypical' diagnosis to PCa where morphology and basal markers are less than optimal in resolving the diagnosis.     

Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization

Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high‐grade prostatic intraepithelial neoplasia (HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, cytogenetic, and histological analyses to delineate clonal, temporal, and spatial relationships between HGPIN and cancer lesions with distinct morphological and molecular features. First, while confirming the previous finding that a substantial fraction of HGPIN lesions associated with ERG‐positive cancers share rearrangements and overexpression of ERG, we found that a significant subset of such HGPIN glands exhibit only partial positivity for ERG. This suggests that such ERG‐positive HGPIN cells either rapidly invade to form adenocarcinoma or represent cancer cells that have partially invaded the ductal and acinar space in a retrograde manner. To clarify these possibilities, we used ERG expression status and TMPRSS2–ERG genomic breakpoints as markers of clonality, and PTEN deletion status to track temporal evolution of clonally related lesions. We confirmed that morphologically distinct HGPIN and nearby invasive cancer lesions are clonally related. Further, we found that a significant fraction of ERG‐positive, PTEN‐negative HGPIN and intraductal carcinoma (IDC‐P) lesions are most likely clonally derived from adjacent PTEN‐negative adenocarcinomas, indicating that such PTEN‐negative HGPIN and IDC‐P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma. These data suggest that invasive adenocarcinoma can morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells. Similar clonal relationships were also seen for intraductal carcinoma adjacent to invasive adenocarcinoma. These findings represent a potentially undervalued indicator of pre‐existing invasive prostate cancer and have significant implications for prostate cancer diagnosis and risk stratification. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1, and Smad4 in benign, premalignant, and malignant human prostate

Deregulation of apoptosis is involved in prostate cancer development and progression. This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions. Prostate tissue was pathologically evaluated, and areas of benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate cancer were identified. Immunohistochemical analysis was performed to determine the expression of p27Kip1, a key cell cycle regulator, transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of prostate cancer. The apoptotic index of the same cell populations was determined using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end labeling assay. Our findings indicate a significant reduction in p27Kip1 immunoreactivity in HGPIN (P<0.0001) and prostate cancer (P<0.0001) compared with the benign tissue. A significant down-regulation was detected in TbetaRII expression in HGPIN and prostate cancer compared with benign prostatic hyperplasia (BPH)(P<0.001). A significant decrease was also observed in Smad4 levels in HGPIN and prostate cancer compared with BPH (P<0.001). Evaluation of the incidence of apoptosis revealed a significant decrease in the apoptotic index among the epithelial cell populations in HGPIN and a further decrease in prostate carcinoma (P<0.01). This reduced apoptotic index correlated with a significant increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN (P<0.05) and the benign lesions of the same prostate specimens (P<0.05). A significant reduction in PSA immunostaining was detected in HGPIN and prostate carcinoma foci compared with the benign glandular epithelia (P<0.001). These results further define deregulation of TGF-beta signaling effectors as a molecular basis for loss of apoptotic control contributing to the development of prostate tumors. Identification of apoptotic regulators in precursor premalignant lesions may have prognostic significance in disease progression as well as therapeutic value for targeting prostate cancer.     

Trends in prostate needle biopsy diagnosis. A ten year experience of a medical center in Taiwan

Prostate cancer has seen a rapid rise in Taiwanese men. The current study was undertaken to evaluate trends of the disease diagnosed on prostate needle biopsy during a ten-year period at the Department of Pathology, Taipei Veterans General Hospital. The study included 8236 men who underwent a total of 9995 prostate needle biopsies at this institute from 1994 to 2003. Pathologic features pertinent to diagnosis of cancer were reviewed and compared for cases diagnosed before and after 1999. There were statistically significant increases of the overall cancer detection rate (from 17.6% to 19.9%), proportion of cases with a Gleason score ≤ 6 (from 16.6% to 40.9%) and focal adenocarcinoma (from 3.0% to 12.8%) in the latter 5 years. The incidence of high-grade prostatic intraepithelial neoplasia (HGPIN) increased from 0.1% to 1.5%. Patients with HGPIN had a significantly higher risk for subsequent cancer discovered on repeat biopsy than did those with a primary benign diagnosis (29.9% versus 13.7%). Despite a relatively lower incidence of cancer and HGPIN in Taiwanese men compared with that reported in Western studies, in recent years we have found an increase of relevant diagnoses, especially cancer of limited extent and lower grade, which may represent the progress in prostate cancer diagnosis.     

Inflammation and preneoplastic lesions in benign prostate as risk factors for prostate cancer

Benign changes ranging from atrophy and inflammation to high-grade prostatic intraepithelial neoplasia (HGPIN) are common findings on prostate core needle biopsies. Although atrophy and inflammation may be precursors of prostate cancer, only HGPIN is currently recommended to be included in surgical pathology reports. To determine whether these benign findings increase prostate cancer risk, we conducted a case-control study nested within a historical cohort of 6692 men with a benign prostate specimen collected between 1990 and 2002. The analytic sample included 574 case-control pairs comprised of cases diagnosed with prostate cancer a minimum of 1 year after cohort entry and controls matched to cases on date and age at cohort entry, race, and type of specimen. The initial benign specimen was reviewed for presence of HGPIN, atrophy (simple, lobular, and partial) and inflammation (glandular and/or stromal). HGPIN significantly increased risk for prostate cancer (odds ratio (OR)=2.00; 95% confidence interval (CI)=1.25-3.20). Inflammation within the stromal compartment was associated with decreased risk (OR=0.66; CI=0.52-0.84), and diffuse stromal inflammation of severe grade had the strongest inverse association with risk (OR=0.21; CI=0.07-0.62). In a model adjusted for prostate-specific antigen (PSA) level at cohort entry and inflammation, simple atrophy was associated with a 33% increased prostate cancer risk that was marginally significant (P=0.03). Clinicians should consider patterns and extent of inflammation when managing high-risk patients with negative biopsy results. Identifying benign inflammatory processes that underlie high PSA levels would help to reduce the number of unnecessary repeated prostate biopsies.     

抗体鸡尾酒AMACR/P63/34βE12在前列腺良恶性病变鉴别诊断中的应用价值

目的:探讨抗体鸡尾酒AMACR/P63/34βE12在前列腺良恶性病变鉴别诊断中的应用价值。方法:收集2001~2005年111例前列腺手术切除标本，其中前列腺腺癌39例，高级别前列腺上皮内瘤（high-grade prostatic intraepithelial neoplasias，HGPIN）29例，非典型性腺瘤样增生（atypical adenomatous hyperplasia, AAH）3例，前列腺结节性增生（benign prostatic hyperplasia, BPH）40例。作抗体鸡尾酒AMACR/P63/34βE12的免疫标记，观察3种抗体在各类病变中的表达情况。结果:39例前列腺腺癌AMACR全部呈阳性，癌巢周围无基底细胞残存（P63/34βE12阴性）。29例高级别前列腺上皮内瘤变，14例（48.3%）腺泡上皮AMACR呈阳性，29例腺泡上皮周围有连续或不连续的基底细胞（P63/34βE12阳性）。3例非典型性腺瘤样增生中2例腺泡上皮AMACR呈弱阳性；3例腺泡上皮周围有较连续的基底细胞（P63/34βE12中度阳性）。40例前列腺结节性增生，腺泡上皮AMACR染色均呈阴性，周围有连续的基底细胞（P63/34βE12强阳性）。结论:鸡尾酒抗体AMACR/P63/34βE12标记前列腺组织，能够同时高特异性和敏感性地检测出前列腺腺癌细胞（或非典型增生的腺泡上皮细胞）和基底细胞，为前列腺腺癌与高级别上皮內瘤变、非典型性腺瘤样增生、前列腺结节性增生的鉴别诊断提供有力的证据。     

Is high‐grade prostatic intraepithelial neoplasia (HGPIN) a reliable precursor for prostate carcinoma? Implications for clonal evolution and early detection strategies

High‐grade prostatic intraepithelial neoplasia (HGPIN) is a documented putative precursor lesion for invasive prostate adenocarcinoma. However, the precise mechanisms of the carcinoma's development from HGPIN are unclear. Many studies have attempted a comparative molecular genetic characterisation of HGPIN and its corresponding carcinoma to study this transformation. However, to date, some HGPIN mimickers, such as intraductal carcinoma, which can engage in retrograde colonisation of the prostatic acini in an HGPIN‐like manner, have been described. In this work, we hypothesise that the lesion formerly known as HGPIN adjacent to invasive carcinoma does not necessarily represent its respective precursor lesion. This hypothesis stems from recent morphological, experimental, and theoretical evidence on the development of tumour clonality, as well as recent studies outlining the three‐dimensional architecture of prostate adenocarcinomas (most importantly, their interconnection with the tumoural glandular system). Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Can molecular markers stratify the diagnostic value of high-grade prostatic intraepithelial neoplasia?

The diagnostic performance of isolated high-grade prostatic intraepithelial neoplasia in prostatic biopsies has recently been questioned, and molecular analysis of high-grade prostatic intraepithelial neoplasia has been proposed for improved prediction of prostate cancer. Here, we retrospectively studied the value of isolated high-grade prostatic intraepithelial neoplasia and the immunohistochemical markers α-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67 for better risk stratification of high-grade prostatic intraepithelial neoplasia in our local Swiss population. From an initial 165 diagnoses of isolated high-grade prostatic intraepithelial neoplasia, we refuted 61 (37%) after consensus expert review. We used 30 reviewed high-grade prostatic intraepithelial neoplasia cases with simultaneous biopsy prostate cancer as positive controls. Rebiopsies were performed in 66 patients with isolated high-grade prostatic intraepithelial neoplasia, and the median time interval between initial and repeat biopsy was 3 months. Twenty (30%) of the rebiopsies were positive for prostate cancer, and 10 (15%) showed persistent isolated high-grade prostatic intraepithelial neoplasia. Another 2 (3%) of the 66 patients were diagnosed with prostate cancer in a second rebiopsy. Mean prostate-specific antigen serum levels did not significantly differ between the 22 patients with prostate cancer and the 44 without prostate cancer in rebiopsies, and the 30 positive control patients, respectively (median values, 8.1, 7.7, and 8.8 ng/mL). None of the immunohistochemical markers, including α-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67, revealed a statistically significant association with the risk of prostate cancer in repeat biopsies. Taken together, the 33% risk of being diagnosed with prostate cancer after a diagnosis of high-grade prostatic intraepithelial neoplasia justifies rebiopsy, at least in our not systematically prostate-specific antigen-screened population. There is not enough evidence that immunohistochemical markers can reproducibly stratify the risk of prostate cancer after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia.     

PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome

Overexpression of the pro-survival protein heme oxygenase-1 (HO-1) and loss of the pro-apoptotic tumour suppressor PTEN are common events in prostate cancer (PCA). We assessed the occurrence of both HO-1 expression and PTEN deletion in two cohorts of men with localized and castration-resistant prostate cancer (CRPC). The phenotypic cooperation of these markers was examined in preclinical and clinical models. Overall, there was a statistically significant difference in HO-1 epithelial expression between benign, high-grade prostatic intraepithelial neoplasia (HGPIN), localized PCA, and CRPC (p < 0.0001). The highest epithelial HO-1 expression was noted in CRPC (2.00 ± 0.89), followed by benign prostate tissue (1.49 ± 1.03) (p = 0.0003), localized PCA (1.20 ± 0.95), and HGPIN (1.07 ± 0.87) (p < 0.0001). However, the difference between HGPIN and PCA was not statistically significant (p = 0.21). PTEN deletions were observed in 35/55 (63.6%) versus 68/183 (37.1%) cases of CRPC and localized PCA, respectively. Although neither HO-1 overexpression nor PTEN deletions alone in localized PCA showed a statistically significant association with PSA relapse, the combined status of both markers correlated with disease progression (log-rank test, p = 0.01). In a preclinical model, inhibition of HO-1 by shRNA in PTEN-deficient PC3M cell line and their matched cells where PTEN is restored strongly reduced cell growth and invasion in vitro and inhibited tumour growth and lung metastasis formation in mice compared to cells where only HO-1 is inhibited or PTEN is restored. In summary, we provide clinical and experimental evidence for cooperation between epithelial HO-1 expression and PTEN deletions in relation to the PCA patient's outcome. These findings could potentially lead to the discovery of novel therapeutic modalities for advanced PCA.     

Multiple therapeutic and preventive effects of 3,3＇-diindolylmethane on cancers including prostate cancer and high grade prostatic intraepithelial neoplasia

Cruciferous vegetables belong to the plant family that has flowers with four equal-sized petals in the pattern of a crucifer cross.These vegetables are an abundant source of dietary phytochemicals,including glucosinolates and their hydrolysis products such as indole-3-carbinol（I3C） and 3,3＇-diindolylmethane（DIM）.By 2013,the total number of natural glucosinolates that have been documented is estimated to be 132.Recently,cruciferous vegetable intake has garnered great interest for its multiple health benefits such as anticancer,antiviral infections,human sex hormone regulation,and its therapeutic and preventive effects on prostate cancer and high grade prostatic intraepithelial neoplasia（HGPIN）.DIM is a hydrolysis product of glucosinolates and has been used in various trials.This review is to provide an insight into the latest developments of DIM in treating or preventing both prostate cancer and HGPIN.