High-grade Prostatic Intraepithelial Neoplasia Foci Research Articles

Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear. We performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2:ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason patterns 3 and 4 foci, using microdissection and targeted deep-sequencing. A total of 32 tumor-specific mutated sites were successfully amplified and sequenced, including 25 truncal mutations and 7 mutations that were specific to either the Gleason pattern 3 or pattern 4 foci. All six HGPIN foci shared the same tumor-specific TMPRSS2:ERG fusion breakpoint, establishing that they were all clonally related to the adjacent invasive tumor. Among the 32 gene targets mutated in the invasive tumor, only mutation of the OR2AP1 gene, a truncal mutation, was found in a single focus of HGPIN. The remaining gene targets that were successfully sequenced were wild-type in all other HGPIN foci. This study demonstrates the feasibility of targeted mutation profiling of HGPIN lesions, which will be important to understand PCa tumorigenesis. The results in this case, showing a remarkable absence of truncal mutations in HGPIN lesions bearing the tumor-specific ERG fusion, indicate HGPIN lesions may be relatively stable genetically and argue against a stepwise clonal evolution model of HGPIN to PCa. Prostate 76:1227-1236, 2016. © 2016 Wiley Periodicals, Inc.

Multiparametric MR can identify high grade prostatic intraepithelial neoplasia (HGPIN) lesions and predict future detection of prostate cancer in men with a negative initial prostate biopsy

PurposeThis study aims to determine the pre-biopsy diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI) characteristics of patients with high-grade prostatic intraepithelial neoplasia (HGPIN) and perform follow-up studies in these patients to assess the clinical implications. Materials and methodsOne hundred sixteen men with prostate specific antigen between 4 and 10ng/ml underwent pre-biopsy MR examinations. Nine of them had HGPIN lesions without concomitant prostate cancer (PCa) on biopsy. Apparent diffusion coefficient (ADC) and metabolite ratio [Citrate/(Choline+Creatine)] were calculated and these 9 patients were followed to determine the clinical outcomes. ResultsMean ADC for HGPIN foci was 1.01±0.16×10−3mm2/s while for the normal peripheral zone it was 1.69±0.25×10−3mm2/s (p<0.005). Mean metabolite ratio for voxels in the HGPIN region of initial biopsy was 0.24±0.16 while for the normal peripheral zone the value was 2.66±1.57 (p<0.005). Four of 5 patients who were available for follow-up were detected to have prostate cancer on repeat biopsy. No significant change in metabolite ratio and PSA was observed while ADC showed further reduction on follow-up. ConclusionHGPIN foci have ADC and metabolite ratio values similar to adenocarcinoma prostate, indicating that such patients have a high likelihood of developing cancer. DWI may help identify such men who may be candidates for close follow-up.

ERG and PTEN status of isolated high-grade PIN occurring in cystoprostatectomy specimens without invasive prostatic adenocarcinoma

High-grade prostatic intraepithelial neoplasia (HGPIN) is widely believed to represent a precursor to invasive prostatic adenocarcinoma. However, recent molecular studies have suggested that retrograde spread of invasive adenocarcinoma into pre-existing prostatic ducts can morphologically mimic HGPIN. Thus, previous molecular studies characterizing morphologically identified HGPIN occurring in radical prostatectomies or needle biopsies with concurrent invasive carcinoma may be partially confounded by intraductal spread of invasive tumor. To assess ERG and PTEN status in HGPIN foci likely to represent true precursor lesions in the prostate, we studied isolated HGPIN occurring without associated invasive adenocarcinoma in cystoprostatectomies performed at Johns Hopkins between 2009 and 2014. Of 344 cystoprostatectomies, 33% (115/344) contained invasive prostatic adenocarcinoma in the partially submitted prostate (10 blocks/case on average) and were excluded from the study. Of the remaining cases without sampled cancer, 32% (73/229) showed 133 separate foci of HGPIN and were immunostained for ERG and PTEN using genetically validated protocols. Of foci of HGPIN with evaluable staining, 7% (8/107) were positive for ERG. PTEN loss was not seen in any HGPIN lesion (0/88). Because these isolated HGPIN foci at cystoprostatectomy are unlikely to represent retrograde spread of invasive tumor, our study suggests that ERG rearrangement, but not PTEN loss, is present in a minority of potential neoplastic precursor lesions in the prostate.

Association of ring box-1 protein overexpression with clinicopathologic prognostic parameters in prostate carcinoma

AimTo determine the expression of Ring Box-1 (RBX-1) protein in prostate carcinoma (PCa) and the association between RBX-1 expression and clinicopathologic prognostic parameters. Material and methodsRelevant data such as age, preoperative serum PSA values, and tumor stage were obtained from 51 patients’ with PCa record who underwent radical prostatectomy between January 2010 and March 2014. Hematoxylin-eosin stained pathology slides were evaluated by 2 pathologists blinded to patients’ data in order to determine Gleason grade groups, tumor stage, tumor volume, capsule invasion, lymphovascular invasion, perineural invasion, and seminal vesicle invasion. Immunoreactivity scoring system (IRS) was used to determine RBX-1 expressions. ResultsA statistically significant difference was determined in terms of RBX-1 expression between non tumoral prostate tissue, high grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma foci (P = 0.001). RBX-1 expression in the Gleason pattern 4 was higher than the Gleason pattern 3 and H-PIN foci as well as non tumoral prostate tissue. Likewise, in cases with PSA levels of>10.1ng/ml, RBX-1 expression was higher than those≤10ng/ml. Moreover, RBX-1 expression of stage II cases was higher than stage I (P = 0.019), RBX-1 expression of stage III higher than stage I cases (P = 0.044). However, RBX-1 expression was not related with clinicopathologic parameters including patient age, tumor volume, lymphovascular invasion, perineural invasion, seminal vesicle invasion, or capsule invasion. ConclusionsRBX-1 protein is overexpressed in PCa and associated with clinicopathologic prognostic parameters related with biological potential of the aggressive disease. Further studies of basic and molecular science are needed to reveal clinical and therapeutic implications of RBX-1 in PCa.

Evaluation of tissue PCA3 expression in prostate cancer by RNA in situ hybridization—a correlative study with urine PCA3 and TMPRSS2-ERG

PCA3 is a prostate-specific non-coding RNA, with utility as a urine-based early detection biomarker. Here, we report the evaluation of tissue PCA3 expression by RNA in situ hybridization in a cohort of 41 mapped prostatectomy specimens. We compared tissue PCA3 expression with tissue level ERG expression and matched pre-prostatectomy urine PCA3 and TMPRSS2-ERG levels. Across 136 slides containing 138 foci of prostate cancer, PCA3 was expressed in 55% of cancer foci and 71% of high-grade prostatic intraepithelial neoplasia foci. Overall, the specificity of tissue PCA3 was >90% for prostate cancer and high-grade prostatic intraepithelial neoplasia combined. Tissue PCA3 cancer expression was not significantly associated with urine PCA3 expression. PCA3 and ERG positivity in cancer foci was positively associated (P<0.01). We report the first comprehensive assessment of PCA3 expression in prostatectomy specimens, and find limited correlation between tissue PCA3 and matched urine in prostate cancer.

High‐Grade Prostatic Intraepithelial Neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: Existence of HGPIN near prostate cancer

High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa.

Cortactin is associated with tumour progression and poor prognosis in prostate cancer and SIRT2 other than HADC6 may work as facilitator in situ

ObjectiveCortactin acts as a prominent substrate of histone deacetylases (HDACs) and plays important roles in tumour progression in several human cancers. However, the clinical significance of its expression in human...

High‐resolution genome‐wide copy‐number analysis suggests a monoclonal origin of multifocal prostate cancer

Many human cancers present as multifocal lesions. Understanding the clonal origin of multifocal cancers is of both etiological and clinical importance. The molecular basis of multifocal prostate cancer has previously been explored using a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multifocal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 48 individual cancer and HGPIN lesions, isolated from 18 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 13 informative cases displaying multiple tumor foci. In addition, individual HGPIN lesions in the two multifocal-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this study and each was detected in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multifocal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci and may further progress to multifocal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multifocal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis.

Value of magnetic resonance spectroscopy (MSR) and dynamic contrast-enhanced magnetic resonance (DCEMR) imaging for the characterization of high-grade prostatic intraepithelial neoplasia (HGPIN) foci

Background Despite an increasing interest in high-grade prostatic intraepithelial neoplasia (HGPIN), the clinical suspicious aspect of this premalignant lesion remains poorly characterized. The aim of this study was to analyze the magnetic resonance spectroscopy (MSR) and dynamic contrast-enhanced magnetic resonance (DCEMR) imaging features of isolated HGPIN lesions. Materials and methods From January 2007 to January 2009, 330 cases were included in a protocol that involve the use of MSR and DCEMR for the diagnosis of prostate diseases. Of these, 27 patients with isolated (no associated prostate cancer diagnosis) HGPIN histologic diagnosis at the first prostate biopsy were included in the present study. All cases were previously submitted to MSR/DCEMR (1.5 T scanner) and, no later than 10 days to a random 12-core biopsy scheme. Biopsy targeting was done in zones corresponding to those analyzed with MSR and DCEMR. Results In the 27 patients, 30 HGPIN foci with a diameter of 6 mm or greater were analyzed and compared with 27 peripheral zone areas of normal prostate tissue. With MSR, HGPIN foci were characterized by a significantly higher ( P < 0.05) absolute value of choline and choline + creatine/citrate ratio compared with normal tissue. With DCEMR, HGPIN foci were characterized by lower values of all dynamic parameters but differences did not reach statistical significance ( P > 0.05). Conclusions In our experience, HGPIN lesions can be metabolically characterized by MSR through the absolute value of choline and the choline + creatine/citrate ratio.

High-Grade Prostatic Intraepithelial Neoplasia in Patients with Prostate Cancer: MR and MR Spectroscopic Imaging Features—Initial Experience

To retrospectively determine the magnetic resonance (MR) and MR spectroscopic imaging features of high-grade prostatic intraepithelial neoplasia (HGPIN) in patients with prostate cancer. Approval of the committee on human research was obtained, with a waiver of consent for this HIPAA-compliant study. Endorectal MR imaging and MR spectroscopic imaging were performed in 48 men (mean age, 59 years; range, 47-75 years) prior to radical prostatectomy for prostate cancer. T2-weighted signal intensity and metabolic ratios of peripheral zone HGPIN foci of 6 mm or greater in diameter were recorded by two readers with knowledge of step-section histopathologic findings using areas of confirmed normal and cancerous peripheral zone tissue for comparison. A random effects statistical model was used to compare metabolic ratios from normal, HGPIN, and cancer voxels. A total of 123 peripheral zone HGPIN foci with a mean diameter of 3 mm (range, 1-28 mm) were identified in 37 (77%) patients, but only 20 foci in 14 patients had a diameter of 6 mm or greater. Six foci were excluded, yielding 14 large HGPIN lesions from 11 patients in the final statistical analysis. The larger HGPIN foci were not associated with any focal reduction in T2-weighted signal intensity but demonstrated metabolic findings intermediate between normal and cancerous tissue; the mean ratios of choline (Cho) to creatine (Cr) for normal, HGPIN, and cancer were 0.92, 1.75, and 1.99, respectively, (P < .01), and the corresponding ratios of Cho plus Cr to citrate were 0.34, 0.50, and 0.78 (P < .01). HGPIN is metabolically intermediate between normal peripheral zone tissue and prostate cancer at MR spectroscopic imaging but does not manifest any MR imaging abnormality and is rarely of sufficient size to cause substantial error in evaluation of peripheral zone tumor extent in patients with prostate cancer.

Transrectal sonographic features of prostatic intraepithelial neoplasia: Correlation with pathologic findings

This study was conducted to evaluate the transrectal sonographic (TRUS) features of prostatic intraepithelial neoplasia (PIN) by comparing the histopathologic results with TRUS findings in patients who had undergone TRUS-guided prostate biopsy. From an initial set of 307 patients who underwent TRUS-guided prostate biopsy, TRUS findings for 44 patients whose pathologic results were consistent with PIN were reviewed retrospectively. Among these 44 patients, 12 had only PIN, 20 PIN associated with prostatitis, and 12 PIN associated with prostate cancer foci. After exclusion of the foci that included PIN associated with prostatitis and PIN associated with prostate cancer at the same site, the pathologic results for the core specimens from the 100 PIN foci were correlated with TRUS findings according to their location. The sonographic features sought were hypoechoic areas and regions of heterogeneous echogenicity. Positive TRUS findings were detected in 43% of PIN and 36% of high-grade PIN (HGPIN) focise. For the HGPIN foci with positive TRUS findings, the detected sonographic features were clusters of millimetric hypoechoic foci (CMHF) (53%), hypoechoic areas with well-defined borders (27%), and heterogeneous echogenicity (20%) (not significant). The sensitivity of the presence of CMHF for the diagnosis of HGPIN was only 19%. TRUS-detected CMHF may indicate HGPIN. Because of the limited sensitivity of this finding, TRUS detection of CMHF does not warrant biopsy, although these lesions warrant close monitoring.

Telomerase Activity and Telomerase Subunit Gene Expression Levels Are Not Related in Prostate Cancer: A Real-Time Quantification and In Situ Hybridization Study

Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs ≥7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.

Telomerase reverse transcriptase subunit immunoreactivity: a marker for high-grade prostate carcinoma.

Telomerase, a ribonucleoprotein complex that maintains telomeric DNA, has been detected in 67-93% of prostate carcinomas by telomeric repeat-amplification protocol assay (involving polymerase chain reaction). One study used in situ hybridization in nine patients; however, to date, no immunohistochemical results have been published. From two hospitals, the authors compiled data on 62 patients who underwent prostatectomy from January 1996 to May 2001. Representative tissue sections were immunostained with a polyclonal antibody to telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. Staining was evaluated by two observers and was correlated with grade, stage, and biochemical failure. There were 28 sections from low-grade to intermediate-grade tumors (Gleason score, 3-6), 14 sections with a Gleason score of 3 + 4 = 7, 9 sections with a Gleason score of 4 + 3 = 7, and 11 sections from high-grade tumors (Gleason score, 8-10). From low-grade to high-grade tumors, the four groups described above disclosed nuclear reactivity in 64%, 100%, 100%, and 100% of sections, respectively. Mean percentages of 5%, 15%, 40%, and 51% of nuclei were reactive in the respective groups (P < 0.0001) with intratumoral heterogeneity. The percent of reactive tumor nuclei was not correlated with pathologic stage (P = 0.32) or margin status (P = 0.35). The basal cell layer in sections of high-grade prostatic intraepithelial neoplasia (HGPIN) and benign/atrophic acini was reactive; secretory cells were reactive in 13 of 34 HGPIN foci (38%) in 1-20% of nuclei and were never reactive in benign acini. Lymphocytes and skeletal muscle were reactive. Weak, nonspecific, cytoplasmic staining was noted in benign and tumor acini. Like cytokeratin 34betaE12, nuclear anti-TERT reactivity is a basal cell marker in nonneoplastic prostatic acini. Anti-TERT reactivity is acquired by secretory cells in tumorigenesis, but consistent reactivity is restricted to high-grade carcinoma (Gleason primary pattern >or=4). This histologic evidence suggests that higher grade tumors have maximally activated telomerase and may be most responsive to antitelomerase therapy.