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PubMedDate not supplied

Repeat prostate biopsies following diagnoses of prostate intraepithelial neoplasia and atypical small gland proliferation.

OBJECTIVE: To assess the incidence of diagnosis of high-grade intraepithelial neoplasia or prostate intraepithelial neoplasia (PIN), and atypical small gland proliferation (ASAP) at a uropathology reference center. To assess the indexes and findings on repeat biopsies. MATERIALS AND METHODS: Diagnoses of PIN, ASAP or PIN + ASAP established between January 1, 2001 and December 31, 2003 were searched in our database. We studied repeat biopsies performed up to August 31, 2004. RESULTS: Of 1420 biopsies, ASAP was diagnosed in 26 (1.8%) patients, PIN in 142 (10%) and PIN + ASAP in 40 (2.8%). Repeat biopsies were performed in 98 patients, 16 (61.5%) with ASAP, 53 (37.3%) with PIN and 29 (72.5%) with PIN + ASAP. Carcinoma was diagnosed in 7 cases (43.8%) following a diagnosis of ASAP, 12 (41.4%) of PIN + ASAP and 7 (13.2%) of PIN. The mean interval between repeat biopsies was 299.6 days. There was no difference between groups where cancer was or was not diagnosed on repeat biopsy in relation to age and serum PSA levels. CONCLUSION: Despite explicit recommendations of repeat biopsy on pathology reports and the high incidence of adenocarcinoma on repeat biopsy, re-intervention rates following a diagnosis of PIN, ASAP, PIN + ASAP are low in our setting. The diagnosis that most frequently led to repeat biopsy was PIN + ASAP. Adenocarcinoma was most often diagnosed after the initial diagnosis of ASAP.

Adenocarcinoma↗
PubMed2001

Radical prostatectomy for high grade prostatic intraepithelial neoplasia.

High Grade Prostatic Intraepithelial Neoplasia (HGPIN) has been recognized as the most likely precursor of invasive carcinoma of the prostate. Close surveillance and follow-up are indicated if subsequent procedures fail to identify carcinoma. There is still considerable controversy about the natural history of high grade PIN and most authors agree that its identification should not influence or dictate therapeutic decisions. We performed a prophylactic radical prostatectomy in such a case which has not been reported in the world literature.

Humans↗
PubMed2004

Microvessel density as a molecular marker for identifying high-grade prostatic intraepithelial neoplasia precursors to prostate cancer.

BACKGROUND: Existing clinical data have shown that high-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor to prostate cancer (CaP). Criteria to distinguish HGPIN that progress to CaP from those that do not remain poorly defined. Our objective was to evaluate microvessel density as a molecular marker for distinguishing HGPINs that have the potential of progressing to cancer. MATERIALS AND METHODS: Human prostatic tissue samples were collected randomly from 50 prostatectomy and cystoprostatectomy patients. Formalin-fixed and paraffin-embedded sections were used for immunohistochemical localization of rabbit anti-human von Willebrand factor VIII (vWF) IgG, mouse anti-high molecular weight cytokeratin 34BE-12 in basal cells, and mouse anti-heparan sulphate proteoglycan (HSPG) IgGs in basement membranes associated with benign prostatic hyperplasia (BPH), PIN associated with some BPH (isolated PIN), and PIN associated with CaP. RESULTS: Analysis of immunostaining data showed that PINs could be categorized according to their distributions within and outside 2 standard deviations (SD) of the mean for microvessel density. The average number of microvessels was significantly higher (P < 0.0001) in PINs associated with Gleason score 7 tumors than those associated with Gleason scores 4-6 (P < 0.1328) or 8 and 9 tumors (P < 0.1708). Morphologically, PINs within 2 SD were composed of low- and high-grade type, whereas those outside 2 SD of microvessel density were predominantly of high-grade type. Cytokeratin and HSPG localization patterns also showed differences in PINs found within and outside 2 SD of microvessel density. We found localization of cytokeratin 34BE-12 in basal cells of specimens with BPH alone, isolated PIN, and PIN associated with CaP within 2 SD, whereas many PINs outside 2 SD showed disruptions in cytokeratin localization. The basement membranes of PINs within 2 SD of microvessel density were relatively intact, whereas those outside 2 SD were fragmented. CONCLUSIONS: Our immunostaining data indicates that once HGPIN is found in the initial prostatic biopsy, it should be evaluated for microvessel density by localization of vWF. Our data indicate that characteristics of HGPIN can be augmented by evaluations of cytokeratin and HSPG molecular markers to assess the potential of HGPIN progression to malignancy. When biopsy samples show HGPIN with increased microvessel density and disrupted cytokeratin and HSPG markers, the patient may be a candidate for repeat biopsy. Since our study is limited to 50 prostate tissue samples, we emphasize that our conclusion is tentative and ought to be confirmed in a study with a larger sample size. This is the first report to show that microvessel density may distinguish HGPIN that is a precursor to prostate cancer.

Aged↗
PubMed2005

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.

Aged↗
PubMed1998

Telomerase activity in prostate cancer, prostatic intraepithelial neoplasia, and benign prostatic epithelium.

Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. Telomerase activation has been seen in many immortal cell lines and cancers. Telomerase activity was analyzed in prostate carcinoma; in coexistent prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), atrophy and normal tissue; and in benign prostate glands. Telomerase activity was detected in 80 of 87 (92%) prostate cancers. Forty-one matched samples (from a total of 32 cases) were available for comparative analysis. The presence of telomerase activity in adjacent PIN, BPH, and normal tissue was correlated with telomerase activity in the malignant epithelium. In these adjacent tissues, telomerase activity was found in 11 of 15 (73%) PINs, 13 of 26 (50%) BPHs, and 1 of 6 (16%) atrophy and 4 of 11 (36%) normal tissues. In contrast to the BPH tissue from cancer-bearing glands, all 16 BPH specimens from patients only diagnosed with BPH were telomerase activity negative. In cancer samples, there was no correlation between telomerase activity and Gleason grade or preoperation prostate-specific antigen level. Our data indicate that telomerase activity is present in most prostate cancers. The high rate of telomerase activity in the benign-appearing areas of these glands may be attributed either to the presence of occult cancer cells or to early molecular alterations of cancer that were histologically inapparent.

Humans↗
PubMed2004

Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs.

To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.

Cell Division↗
PubMed1997

Diagnostic distance of high grade prostatic intraepithelial neoplasia from normal prostate and adenocarcinoma.

OBJECTIVE: To develop a distance measure based methodology to support the morphological evaluation of high grade prostatic intraepithelial neoplasia (PIN), a direct precursor of prostate cancer. METHODS: Eight morphological and cellular features were analysed in 20 cases of high grade PIN found in radical prostatectomy specimens from patients with adenocarcinoma. The diagnostic distance was evaluated to measure the extent to which the feature outcomes of the individual high grade PIN cases differed from the expected outcome profile of normal prostate, low and high grade PIN, and cribriform and large acinar adenocarcinoma. The belief value for high grade PIN was evaluated with a Bayesian belief network (BBN). RESULTS: Complete separation existed between the cumulative absolute diagnostic distances of these 20 cases from the prototype feature outcomes of high grade PIN and normal prostate the values for which were < or = 3 (range 0 to 3) and > or = 9 (range 9 to 15), respectively. The distances from low grade PIN (range 3 to 9), cribriform adenocarcinoma (range 2 to 8), and large acinar adenocarcinoma (range 5 to 10) were intermediate and showed overlap in their distribution. When taking into consideration whether the severity of feature changes was increasing or decreasing in comparison with the category prototype outcomes, the cumulative directional diagnostic distances from high grade PIN ranged from -3 to +3. Positive distance values were seen relative to low grade PIN (range +3 to +9) and relative to normal prostate (range +9 to +15). Negative values were found relative to cribriform adenocarcinoma (range -8 to +2). The distance values from large acinar adenocarcinoma ranged from -2 to +4 and partly overlapped with those from the high grade PIN category. A bivariate scattergram derived from both diagnostic distance measures showed excellent separation between the groups' distances. BBN analysis confirmed the morphology based diagnosis. The distance evaluation resulted in 18 cases whose belief value for high grade PIN ranged from 0.60 to 0.87. In the remaining two cases the results of the BBN analysis showed a belief value of 0.50 and 0.57 for low grade PIN and of 0.49 and 0.38 for high grade PIN, respectively. CONCLUSIONS: Distance measure based methodology represents a useful diagnostic decision support tool for the accurate evaluation of high grade PIN.

Adenocarcinoma↗
PubMedDate not supplied

[Intraepithelial prostatic neoplasia: a new dysplastic lesion of the prostate].

Prostatic Intraepithelial Neoplasia were studied retrospectively in 455 cases of surgically resected prostates: 387 benign hypertrophies and 68 adenocarcinomas. The frequency of PIN was highest among prostatic adenocarcinomas well differentiated while the benign hypertrophies showed a lower frequency and a moderate increase with age. The prognostic importance of this lesion in prostatic biopsies is discussed on account of its strong predictive value.

Adenocarcinoma↗
PubMed2001

Prostate cancer detection in men with prior high grade prostatic intraepithelial neoplasia or atypical prostate biopsy.

PURPOSE: We used clinical variables to predict prostate cancer detection on re-biopsy among patients diagnosed with high grade prostatic intraepithelial neoplasia (PIN) or atypia on initial prostate biopsy. MATERIALS AND METHODS: A total of 45 men with atypia and 43 with high grade PIN were eligible for our study. Clinical variables were tested with univariate and multivariate logistic regression to predict who would have cancer on re-biopsy. We also calculated the odds of detecting cancer with various repeat sampling strategies and determined whether the location of initial atypia or high grade PIN is correlated to that of cancer on re-biopsy. RESULTS: Of the patients in the atypia and high grade PIN groups 51% had cancer on re-biopsy. Cancer was diagnosed significantly earlier in the high grade PIN than in the atypia cohort (average 7.5 versus 22.9 months, respectively, p = 0.005). Multivariate logistic modeling showed that digital rectal examination and patient age were independent predictors of cancer in atypia, whereas no variables were significantly predictive for high grade PIN. Of cancers in the atypia and high grade PIN 65% and 74%, respectively, would have been detected if re-biopsy was focused only at the initial site of disease. CONCLUSIONS: Men with atypia or high grade PIN merit close followup because 50% will have cancer on re-biopsy as will those who are older with an abnormal digital rectal examination. Although re-biopsy should focus primarily on the original site of atypia or high grade PIN, cancer detection significantly increases with the sampling of adjacent sites.

Aged↗
PubMedDate not supplied

[Intraepithelial prostatic neoplasia].

44 patients seeked medical advice for low urinary symptoms. Their examination consisted of digital rectal investigation, test for prostate-specific antigen (PSA) in the serum, transurethral ultrasonic investigation, fine needle multifocal biopsy of the prostate. Three groups were identified by the PSA levels. 7 patients of group 1 had PSA up to 6 ng/ml. Cancer was diagnosed in 3 of them, prostatic intraepithelial neoplasia (PIN) in 4 patients. 16 patients of group 2 had PSA within 7-10 ng/ml. In this group only 1 patient had cancer, the rest 15 had PIN. 21 patients of group 3 with PSA at least 10 ng/ml had cancer, benign prostatic hyperplasia, PIN (12, 2 and 7 patients, respectively). 3 patients with high-grade PIN and PSA above 10 ng/ml in 6 months were diagnosed to have adenocarcinoma, in 6 such patients signs of dysplasia disappeared after antiandrogenic therapy. Further investigations on diagnosis and treatment of PIN are desirable.

Biomarkers, Tumor↗
PubMed1994

Apoptotic index as a biomarker in prostatic intraepithelial neoplasia (PIN) and prostate cancer.

Chemoprevention trials in prostate cancer would involve excessively long follow-up if conventional endpoints of efficacy are used. Prostatic intraepithelial neoplasia (PIN) may be an appropriate surrogate endpoint for monitoring outcome during prostate cancer chemoprevention studies. To address the question of whether PIN could be stratified into "stable" PIN and PIN likely to progress to invasive cancer, we selected patients with a single focus of peripheral zone cancer with ipsilateral and contralateral high-grade PIN. Sixteen patients met these criteria from a series of 550 patients treated by radical prostatectomy. We examined the rate of apoptosis in PIN and prostate cancer tissues by quantifying the number of apoptotic bodies per hundred cells (apoptotic index) on hematoxylin and eosin stained histological sections. Significant differences (ANOVA: p < 0.05) were detected between foci of prostatic intraepithelial neoplasia contralateral to the cancer and the cancer itself. There was no difference in the apoptotic index between a given cancer and a focus of PIN ipsilateral to the tumor in the same section. However, the range of apoptotic indices overlapped in all categories. Apoptotic indices appear to parallel the biological activity of PIN and malignant prostatic tissue, but may be of little benefit when used alone in monitoring the outcome of chemopreventive therapy in an individual patient.

Analysis of Variance↗
PubMed2001

Chemoprevention for prostatic carcinoma: The role of flutamide in patients with prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor for prostatic adenocarcinoma. The prevalence of prostatic intraepithelial neoplasia (PIN) increases with advancing age. Autopsy studies suggest that PIN may precede the development of prostatic adenocarcinoma by up to 10 years. As such, HGPIN is believed to be a marker of increased risk. This provides a potential opportunity for chemoprevention. Flutamide is 1 agent with potential activity and limited side effects that may act to prevent or delay the onset of prostatic adenocarcinoma in men with HGPIN. A clinical trial is currently underway to assess the efficacy of flutamide.

Age Factors↗
PubMed2004

Expression of prostate specific membrane antigen (PSMA) in prostatic adenocarcinoma and prostatic intraepithelial neoplasia.

The prostatic membrane antigen (PSMA) is a protein that is expressed in the prostatic epithelium. We studied the expression of PSMA in a series of 55 patients with different stages of prostate cancer and we compared the PSMA staining in prostate cancer cells, in high-grade prostatic intraepithelial neoplasia (PIN) and in histologically benign prostatic epithelium for the same specimen. For this purpose archival paraffin-embedded specimens were studied by immunohistochemistry with a monoclonal antibody 7E11-C5.3 against PSMA using the streptavidin-biotin method. The mean percentage of PSMA immunoreactivity was 56.67% in prostate cancer (CaP) cells, and 48.6% in PIN cells, which was significantly higher than benign-appearing prostatic epithelium (5.72%) (for each pair, p<0.001). PSMA expression was greater in CaP with a higher Gleason score (p=0.01), but no relationship was found with serum PSA value. We conclude that PSMA overexpression is detected in high-grade PIN and is associated with a higher Gleason score of prostate cancer. It is a potential marker for studying carcinogenesis and progression of prostate cancer.

Adenocarcinoma↗
PubMed2005

Prostatic intraepithelial neoplasia: an overview.

Prostatic intraepithelial neoplasia (PIN) is the most established precursor of prostatic carcinoma. The presence of prominent nucleoli within an existing duct structure is an easy way to identify the disorder. Four main patterns of high-grade PIN (HGPIN) have been described: tufting, micropapillary, cribriform, and flat. In addition to exhibiting similar cytologic features, both HGPIN and prostatic carcinoma are associated with increased incidence and severity with age, and with high rates of occurrence in the peripheral zone of the prostate. HGPIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive malignant carcinoma. The clinical significance of HGPIN is that it identifies patients at risk for malignancy. With the increased use of extended biopsy protocols, clinicians are more likely to identify HGPIN and less likely to miss concurrent carcinoma. Androgen deprivation therapy decreases the prevalence and extent of PIN, and may play a role in chemoprevention. Preliminary studies suggest that selective estrogen receptor modulators may also prevent the progression of HGPIN to prostate cancer.

Journal Article↗
PubMedDate not supplied

Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology.

Telomeres are terminal, repeated deoxyribonucleic acid (DNA) sequences that stabilize and protect the ends of the chromosomes. Mounting evidence indicates that by initiating chromosomal instability, short dysfunctional telomeres may be involved in prostate carcinogenesis. Although the exact cause of the telomere shortening observed in prostate cancer remains a mystery, telomere loss is known to occur during cell division and oxidative DNA damage, 2 byproducts of chronic inflammation, which is a common histologic finding in the prostate. In addition to prostate cancer causation, telomeres may also play a role in disease progression, and there are indications that tumor telomere content may prove useful as a prognostic marker. Once established, prostate cancer cells almost invariably activate the telomeric DNA polymerase enzyme telomerase, the detection of which may prove useful for diagnostic purposes. Interestingly, telomerase activity is suppressed in prostate cancer cells after androgen withdrawal, raising the possibility that androgen ablative therapies may re-instigate telomere loss, and consequent genetic instability, in surviving cancer cells, thus contributing to the emergence of an androgen-independent, lethal phenotype. A more thorough understanding of telomere biology as it relates to prostate cancer should provide new opportunities for disease prevention, diagnosis, prognostication, and treatment.

Humans↗
PubMed1999

Subtle morphological and molecular changes in normal-looking epithelium in prostates with prostatic intraepithelial neoplasia or cancer.

BACKGROUND: Prostate cancer develops over an extended period of time. Until recently, the events initiating the process and the developments concomitant with the evolution towards invasive disease were largely unknown. METHODS: Analytical and quantitative methods are applied to provide insights into certain individual molecular events and their effects on the complex multiple feedback system of cellular metabolism and regulation in prostate neoplasia. RESULTS: Prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa) are associated with or possibly preceded by changes in the chromatin of secretory cell nuclei. The changes are detectable with a Bayesian belief network and quantifiable by computer image analysis in prostatic tissue that still appears histologically normal. In addition, normal-looking prostate epithelium shows some molecular changes similar to those present in the associated preneoplastic and neoplastic lesions. Such changes are also occasionally present in normal prostate glands without PIN and cancer. CONCLUSIONS: The subtle morphological and molecular changes of normal-looking epithelium might be seen as the onset of the development of prostatic neoplasia.

Adenocarcinoma↗
PubMed1993

Does high grade prostatic intraepithelial neoplasia result in elevated serum prostate specific antigen levels?

Prior studies have evaluated high grade prostatic intraepithelial neoplasia on biopsy material when undiagnosed carcinoma or benign prostatic hyperplasia (BPH) may have been associated with elevated serum prostate specific antigen (PSA) levels. We studied 65 totally embedded radical prostatectomy specimens with minimal carcinoma (tumor volume 0.5 cc or less) and relatively minimal BPH (gland weight less than 65 gm.). Even for these relatively small glands, PSA showed a significant correlation with gland volume (r = 0.64). To account for BPH, PSA density (PSA divided by gland volume) was also calculated. In these specimens with trivial tumor the tumor volume did not correlate with PSA (r = 0.12) or PSA density (r = 0.23). The volume of high grade prostatic intraepithelial neoplasia also showed no correlation with PSA (r = 0.16) or PSA density (r = 0.14). The 11 cases with extensive high grade prostatic intraepithelial neoplasia (0.50 cc or more) had PSA density values of 0.03 to 0.14, with 10 less than 0.1. Of the 6 cases with PSA density values of 0.1 or more only 1 had a high grade prostatic intraepithelial neoplasia volume of 0.5 cc or more. These results indicate that high grade prostatic intraepithelial neoplasia in and of itself does not account for elevated serum PSA levels. In a patient with high grade prostatic intraepithelial neoplasia on biopsy material and elevated serum PSA values, BPH may account for the elevated serum PSA levels. More likely, because of the association between high grade prostatic intraepithelial neoplasia and carcinoma these patients have undiagnosed carcinoma as the source of the elevated serum PSA values.

Humans↗