High-grade Prostatic Intraepithelial Neoplasia Group Research Articles

Implications of a diagnosis of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) on prostate biopsy: a 5-year follow-up study.

In the era of active surveillance of low- and intermediate-risk prostatic cancer, a reconsideration of the implications of a biopsy report of ASAP and/or HGPIN may be timely. We investigated the implications of a diagnosis of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) on prostate biopsy. The rate of re-biopsy and the incidence of carcinoma on repeat biopsy for benign, HGPIN, and ASAP groups were compared. Mean PSA and PSA velocity was also compared between groups. There was an increased risk of developing prostate cancer in the following 5years with a biopsy diagnosis of ASAP compared to benign (20% vs 5.9%, p = 0.009), and with a biopsy of HGPIN compared with benign (14.8% vs 5.9%, p = 0.005). The frequency of repeat biopsy following a diagnosis of ASAP (54.2%) vs. HGPIN (37%) was not significantly different (p = 0.079). The risk of developing prostate cancer was highest following a biopsy with concomitant ASAP and HGPIN compared to benign (50% vs 5.9%, p < 0.001). There was no significant difference in PSA values between the 3 diagnostic groups at the time of initial biopsy (p = 0.206). The findings of this study suggest that a biopsy diagnosis of ASAP ± HGPIN, on either initial or surveillance biopsy, provides support for earlier repeat mpMRI and/or re-biopsy. This may assist in directing to early re-biopsy those patients likely to have intermediate- and high-risk prostate cancer.

Outcomes of Prostate Atypical Small Acinar Proliferation and High-Grade Prostate Intraepithelial Neoplasm Patients

Objective: Atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two pathological findings occasionally noted in prostate biopsies. Previous Western studies reported that they were associated with prostate cancer. However, none Taiwanese series report the subsequent cancer detection in ASAP and HGPIN patients. This study aimed to examine the results of repeated biopsies in the patients with ASAP and HGPIN. Materials and Methods: A total of 220 consecutive patients with ASAP and/or HGPIN at our institute between January 1990 and December 2010 were enrolled. Patient demographics and clinical information were extracted from the electronic database of our institute. Prostate biopsies were performed through transrectal ultrasound guidance. The patients who had concurrent prostate cancer (n = 51) and no repeated prostate biopsies (n = 103) were excluded from the study. Patients with biopsy pathologies reporting low-grade prostatic intraepithelial neoplasia (n = 2) were also excluded. The remaining 64 patients were available for the final analysis. Results: Nearly, 38, 24, and 2 patients were initially diagnosed as ASAP, HGPIN, and ASAP along with HGPIN, respectively. After 10 years of follow-up, 36.8% patients in ASAP group developed prostate cancer, while 16.7% in HGPIN group and 100% in ASAP + HGPIN group. Median time to developing prostate cancer were 20 months in ASAP group, 31 months in HGPIN group, and 48 months in ASAP + HGPIN group. There was no significant difference of prostate cancer development between ASAP and HGPIN group (P = 0.291). Only older age, classified by 65 years, was significantly associated with a higher detection rate of prostate cancer. Conclusion: Patients with the initial diagnosis of ASAP or PIN has a high risk of developing prostate cancer. Therefore, those patients should be well announced and followed regularly.

Multiple cores of high grade prostatic intraepithelial neoplasia and any core of atypia on first biopsy are significant predictor for cancer detection at a repeat biopsy.

PurposeTo investigate the differences in the cancer detection rate and pathological findings on a second prostate biopsy according to benign diagnosis, high-grade prostatic intraepithelial neoplasia (HGPIN), and atypical small acinar proliferation (ASAP) on first biopsy.Materials and MethodsWe retrospectively reviewed the records of 1,323 patients who underwent a second prostate biopsy between March 1995 and November 2012. We divided the patients into three groups according to the pathologic findings on the first biopsy (benign diagnosis, HGPIN, and ASAP). We compared the cancer detection rate and Gleason scores on second biopsy and the unfavorable disease rate after radical prostatectomy among the three groups.ResultsA total of 214 patients (16.2%) were diagnosed with prostate cancer on a second biopsy. The rate of cancer detection was 14.6% in the benign diagnosis group, 22.1% in the HGPIN group, and 32.1% in the ASAP group, respectively (p<0.001). When patients were divided into subgroups according to the number of positive cores, the rate of cancer detection was 16.7%, 30.5%, 31.0%, and 36.4% in patients with a single core of HGPIN, more than one core of HGPIN, a single core of ASAP, and more than one core of ASAP, respectively. There were no significant differences in Gleason scores on second biopsy (p=0.324) or in the unfavorable disease rate after radical prostatectomy among the three groups (benign diagnosis vs. HGPIN, p=0.857, and benign diagnosis vs. ASAP, p=0.957, respectively).ConclusionsPatients with multiple cores of HGPIN or any core number of ASAP on a first biopsy had a significantly higher cancer detection rate on a second biopsy. Repeat biopsy should be considered and not be delayed in those patients.

The relation of beclin 1 and bcl-2 expressions in high grade prostatic intraepithelial neoplasia and prostate adenocarcinoma: A tissue microarray study

The aim of the present study was to evaluate the expressions of beclin 1 and bcl-2 in prostate cancer (PC) and high grade prostatic intraepithelial neoplasia (HGPIN), and to investigate their relationship with clinicopathological parameters. The study included 30 benign prostatic hyperplasia (BPH), 40 HGPIN and 106 primary PC cases. The expressions of beclin 1 and bcl-2 were assessed semiquantitatively based on both the percentage and intensity of positive staining cells. Beclin 1 was positive in 27 (90%) BPH, 37 (92.5%) HGPIN, and 90 (84.9%) PC cases (p>0.05). Bcl-2 immunostaining was detected in 99 (93.4%) PC, 37 (92.5%) HGPIN, and 9 (30%) BPH cases (p<0.0001). Regarding expression scores, beclin 1 was significantly lower in PC cases than in the HGPIN and BPH groups (p<0.0001), and it was also negatively correlated with Gleason score (p=0.004, r=−0.274). Bcl-2 expression score was significantly higher in PC than in the other groups (p<0.0001), and also positively correlated with Gleason score (p<0.0001, r=0.425). Furthermore, a negative correlation was found between bcl-2 and beclin 1 expression scores in PC cases (p=0.006, r=−0.265). Our results suggest an association between bcl-2 and beclin 1 expressions in malignant transformation of prostate tissue and also in regulating PC cell differentiation, progression and the aggressiveness of PC.

What is the fate of repeat biopsies after diagnosis of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation?

In this study, we reviewed the outcomes of patients undergoing repeat biopsies, following initial diagnosis of high grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) and compared the pathological results to second biopsies due to increased PSA. We retrospectively assessed transrectal ultrasound guided prostate biopsy (TRUSBP) database at our institution between January 2003 and March 2011. Nonparametric tests and binary logistic regression analysis was performed. Among the 1451 TRUSBP taken, 30.4%, 6.4%, 4.7% were diagnosed as prostate carcinoma (PCa), HGPIN, ASAP, respectively. Among patients with HGPIN and ASAP, 68 patients and 48 patients with subsequent biopsies were selected. We also selected 128 patients with diagnosis of benign prostatic tissue (BPT) and subsequent biopsies due to increased PSA. After second biopsy, HGPIN and PCa reported in 29.4% and 20.6%, respectively in HGPIN group; ASAP and PCa was reported in 25% and 37.5%, respectively in ASAP group. Significant increase in PCa rate was reported on second biopsy in ASAP group when compares to HGPIN group (37.5% vs 20.6%, p=0.04) and BPT group (37.5% vs 18.8%, p=0.009). Overall, PCa was diagnosed in 26.5%, 45.8%, 18.8% in HGPIN, ASAP, BPT groups, respectively. Significant difference in PCa rate was detected only in ASAP group. PSAD has significant effects on PCa in all groups (p=0.001 and p=0.01, respectively). HGPIN is no longer associated with higher risk of cancer. Patients should be followed with yearly prostate specific antigen (PSA) and digital rectal examination (DRE). Repeat biopsy should be made as soon as feasible in patients with ASAP.

Concomitant High-Grade Prostatic Intraepithelial Neoplasia Is Associated with Good Prognosis Factors and Oncologic Outcome after Radical Prostatectomy

Objectives: To assess correlations between concomitant high-grade prostatic intraepithelial neoplasia (HGPIN), pathological features and oncologic outcomes after radical prostatectomy (RP). Material and Methods: We prospectively collected a single-institution database of 2,351 patients who underwent RP between 1998 and 2011. Results: 1,272 (54.1%) patients had HGPIN on specimens. The mean follow-up was 28 months. Presence of HGPIN was significantly associated with a favorable preoperative risk status and with pathological factors of poor prognosis in RP specimens. Patients without HGPIN had a worse biochemical recurrence-free survival compared with those with HGPIN in RP specimen (log-rank test: p = 0.015). The 3-year RFS rate was 73.9% for the HGPIN group versus 67.2%. The absence of HGPIN was also significantly correlated with the use of androgen deprivation treatment during the follow-up (p < 0.001). In Cox multivariate analysis, taking into account the other prognostic pathological factors, HGPIN was not an independent predictive factor for PSA failure (p = 0.868). Conclusion: HGPIN is associated with factors of good prognosis but fails to show independent significance when classical pathological prognostic factors are taken into account.

Steroid hormone receptors, matrix metalloproteinases, insulin‐like growth factor, and dystroglycans interactions in prostatic diseases in the elderly men

The aim of this study was to evaluate the reactivity of steroid hormone receptors (SHRs), dystroglycans (DGs), matrix metalloproteinases (MMPs), insulin-like growth factor receptor (IGFR-1), and laminin (Lam) in both prostatic stromal and epithelial compartments showing different diseases in elderly men. Sixty prostatic samples were obtained from 60- to 90-year-old patients (mean 63 years) with and without prostatic lesions from Hospital of the School of Medicine, State University of Campinas (UNICAMP). The Samples were divided into standard (no lesions); high grade prostatic intraepithelial neoplasia (HGPIN); prostatic cancer (PC); and benign prostatic hyperplasia (BPH) groups. The samples were submitted to immunohistochemistry and Western blotting analyses. Research Ethics Committee of the School of Medicine, University of Campinas/UNICAMP (number 0094.0.146.000-08). The results showed increased IGFR-1 and MMPs protein levels in the PC and HGPIN groups. Decreased αDG and βDG protein levels were verified in the PC and HGPIN groups. Androgen receptor (AR) reactivity was similar among all groups. Estrogen receptor α (Erα) immunoreactivity was more intense in the epithelium in the PC and HGPIN groups. Estrogen receptor β (ERβ) immunoreactivity was weak in the epithelium of the HGPIN and PC groups. To conclude, there was an association among IGFR-1, MMPs, and SHRs, indicating IGFR-1 as a target molecule in prostate therapy, considering the IGF proliferative properties. Also, the distinct SHRs reactivities in the lesions in both prostatic compartments indicated different paracrine signals and pointed out the importance of estrogenic pathways in the activation of these disorders.

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.

The role of high-grade prostatic intraepithelial neoplasia for biochemical relapse of prostate carcinoma after radical prostatectomy

The objective of the study was to evaluate the relationship between high-grade intraepithelial neoplasia diagnosed after radical retropubic prostatectomy and the clinical and pathological characteristics of prostate cancer, and to evaluate the time to biochemical relapse of the disease within the groups of high-grade prostatic intraepithelial neoplasia (HGPIN) and non-HGPIN patients. Patients, clinically diagnosed with local prostate carcinoma at the Clinic of Urology, Kaunas University of Medicine, during 2003-2007 and treated with radical retropubic prostatectomies, were distributed into two groups according to the HGPIN detected in the postoperative material: HGPIN and non-HGPIN. The two groups were compared in terms of preoperative and postoperative characteristics. The patients who were followed up for at least 12 months were included into the study. The biochemical relapse of prostate cancer was determined if there were two consecutive rises of prostate-specific antigen (PSA) level above 0.2 ng/mL or according to the attending physician's opinion, there was a need for adjuvant treatment even with onetime rise of PSA level above 0.2 ng/mL. There was no significant difference between the HGPIN and non-HGPIN groups in terms of time to biochemical relapse and frequency of biochemical relapses, time before surgery, the timing of the HGPIN diagnosis, age, or PSA level. After radical prostatectomy, patients in the HGPIN group were found to have significantly more often poorer cancer cell differentiation according to the Gleason score (≥7 vs. <7; P=0.001) and higher TNM stage (T3a,b vs. T2a,b,c; P=0.001). Fewer positive resection margins were diagnosed in the HGPIN group (P=0.05). The groups did not differ in terms of the degree of differentiation according to the Gleason score or perineural invasion (P=0.811 and P=0.282, respectively). HGPIN was more often associated with the characteristics of the poor prognosis for relapse of prostate cancer: poorer tumor cell differentiation according to the Gleason score and more cases of higher TNM stage. HGPIN did not have any influence on biochemical relapse of the disease during the short-term follow-up.

Is high grade prostatic intraepithelial neoplasia still a risk factor for adenocarcinoma in the era of extended biopsy sampling?

There is controversy regarding the role of high grade prostatic intraepithelial neoplasia (HGPIN) on prostatic needle biopsy (PNB) as a risk factor for prostatic adenocarcinoma. We utilise a large Canadian database to determine whether HGPIN detected on extended PNB is a significant risk factor for prostatic adenocarcinoma. Pathological findings from PNBs from 12 304 men who underwent initial PNB during an 8 year period were analysed. Patients were included in the study if their initial diagnosis was HGPIN alone or a benign diagnosis, if at least one follow-up PNB was performed, and if both the initial and follow-up PNB contained at least 10 prostate cores. In the benign group of 105 patients and the HGPIN group of 120 patients, 14.1% and 20.8% were diagnosed with prostatic adenocarcinoma, respectively. When the HGPIN group was further subdivided into unifocal (1 core) and multifocal (>or=2 cores) groups, 9.4% and 29.9% developed prostatic adenocarcinoma, respectively (p < 0.0001). Cox regression analysis adjusting for age and prostate specific antigen (PSA) confirms the significance of HGPIN as a risk factor for prostatic adenocarcinoma (p = 0.0045). Patients with an initial diagnosis of multifocal HGPIN on extended PNB are at a greater risk for subsequent prostatic adenocarcinoma than those with unifocal HGPIN or benign diagnoses.

Prostatic diseases in the senescence: structural and proliferative features

Senescence is one of the main aetiological factors which are responsible for natural androgen ablation in men and occurrence of prostatic diseases. However, it is unclear how the prostatic lesions are signallised in the prostate. Thus, the aim of this study is to characterise the structural, the ultrastructural and the proliferative aspects of the peripheral prostatic zone in the elderly men with and without diagnoses of prostatic lesions and with potential precursors of prostate cancer. Sixty samples of prostatic tissue, from 60 to 90-year-old patients with and without lesions obtained from autopsied or prostatectomised patients were divided into four groups (15 samples per group): standard group (no lesions), benign prostatic hyper-plasia group, high-grade prostatic intra-epithelial neoplasia group and prostatic carcinoma group. The samples were submitted to morphometrical, structural and ultrastructural analyses in addition to cellular apoptosis and proliferative analyses. The results showed morphological damages in the stroma and cellular organelles involved in the secretory process of the prostate. Moreover, the prostatic lesions in elderly men demonstrated disturbance in the proliferation/apoptosis rate, indicating a prevalence of the proliferative process. Finally, the imbalance in prostatic stroma-epithelium interaction was a harmful feature in the elderly men as a result of structural changes, which are crucial factors for the development and progression of carcinogenesis.

PROGNOSTIC SIGNIFICANCE OF HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA AND ATYPICAL SMALL ACINAR PROLIFERATION IN THE CONTEMPORARY ERA

High grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) in the sextant biopsy had been associated with a high risk of prostate cancer. We determined whether the extended biopsy schemes used in the contemporary era have altered the prognostic value of these lesions at repeat biopsies. From 1998 to 2003, 105 of 1,188 men had at least 1 repeat extended biopsy due to the presence of HGPIN (33 men) or ASAP (72 men) in a previous extended biopsy. Median biopsy interval for HGPIN and ASAP was 15 and 10 weeks (p <0.05), respectively. Differences in cancer detection rates were analyzed using the Pearson chi-square test. In the HGPIN group only 1 of 22 (4.5%) men had cancer on 1st repeat biopsy and 0 of 11 men had cancer on 2nd repeat biopsy. In men with ASAP 19 of 53 (36%, p <0.005) had cancer on 1st repeat biopsy, and 3 of 19 (16%) had cancer on 2nd repeat biopsy. Cancer was confined to a single core in 16 of 22 (73%) men. Median Gleason score was 6. Patient age, digital rectal examination status, prostate specific antigen, free prostate specific antigen, number of cores and biopsy interval were not independent predictors of cancer in men with ASAP. HGPIN found in the contemporary extended biopsy does not warrant repeat biopsy. ASAP continues to be associated with a high risk of cancer and requires at least 1 repeat biopsy using the extended biopsy scheme.