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PubMedDate not supplied

Prevalence of high-grade prostatic intraepithelial neoplasia and its relationship to serum prostate specific antigen.

OBJECTIVE: We assessed the incidence of high-grade prostatic intraepithelial neoplasia (HGPIN) in prostates removed for bladder cancer, and evaluated its correlation with preoperative serum prostate specific antigen (PSA). MATERIALS AND METHODS: We reviewed the histology of the prostate from men who underwent cystoprostatectomy for bladder cancer without known prostate pathology prior to surgery. Preoperative serum PSA levels in patients with HGPIN were analyzed. RESULTS: 61 cystoprostatectomy specimens from May 1992 to April 1999 were reviewed. High-grade prostatic intraepithelial neoplasia (PIN) was found in 46/61 (75%) of the prostate specimens, including 21/21 (100%) patients with prostatic cancer, and 25/40 (63%) patients without prostatic cancer. The mean serum PSA in men with PIN without evidence of prostatic adenocarcinoma was 1.9 ng/mL (SD=2.026). CONCLUSION: The incidence of isolated high-grade PIN was 63%. The presence of high-grade PIN does not result in a significant elevation of serum PSA.

Journal Article↗

PubMed2006

Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis.

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma, but the frequency and timing of epigenetic changes found in prostate carcinogenesis has not been extensively documented. Thus, the promoters of three genes (APC, GSTP1, and RARbeta2) involved in prostate carcinogenesis were tested by quantitative methylation-specific PCR in tissue DNA from 30 prostate carcinomas, 128 high-grade PIN lesions, and 30 normal prostate tissue samples dissected from 30 radical prostatectomy specimens using laser capture microdissection. The percentage of methylated alleles (PMA) was calculated for each gene, and hierarchical cluster analysis was used to define the degree of similarity of epigenetic alterations among the various samples. We found that PMA values of APC and RARbeta2 were higher than those of GSTP1 in all three types of tissue samples and median PMA values for all three genes were higher in prostate cancer. By cluster analysis, 26 of 30 prostate carcinomas and 82 of 128 high-grade PIN lesions were grouped in the "high methylation" branch, whereas 24 of 30 normal prostate tissue samples were allocated in the "low methylation" branch. Although high-grade PIN lesions are epigenetically more similar to prostate carcinoma than to normal prostate tissue, paired prostate carcinoma and high-grade PIN lesions did not always segregate together. We concluded that APC and RARbeta2 hypermethylation is frequent in normal prostate tissue and the progressive enrichment in cells carrying methylated alleles observed in high-grade PIN and prostate carcinoma is consistent with clonal progression. Because GSTP1 promoter methylation is mainly observed in prostate carcinoma and some high-grade PIN lesions, it represents an important marker for the transition of in situ to invasive neoplasia.

Aged↗

PubMed1995

Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies.

PURPOSE: High grade prostatic intraepithelial neoplasia is considered the most likely precursor of prostatic adenocarcinoma. However, the natural history and predictive value of prostatic intraepithelial neoplasia for cancer are unknown. MATERIALS AND METHODS: To examine the predictive value of high grade prostatic intraepithelial neoplasia, we conducted a retrospective clinic based comparative study of 100 patients with high grade prostatic intraepithelial neoplasia and 112 without prostatic intraepithelial neoplasia on needle biopsies matched for digital rectal examination findings, patient age and serum prostate specific antigen level. Only patients who had 1 or more followup biopsies were included. RESULTS: Adenocarcinoma was identified in 35% of subsequent biopsies from patients with prostatic intraepithelial neoplasia, compared with 13% of control biopsies. The likelihood of finding cancer increased as the interval from initial biopsy increased. High grade prostatic intraepithelial neoplasia, patient age and serum prostate specific antigen concentration were jointly highly significant predictors of cancer, with prostatic intraepithelial neoplasia providing the highest risk ratio of 14.93 (95% confidence intervals 5.6 to 39.8). No other candidate predictor was significant, including digital rectal examination findings, transrectal ultrasound results, amount of prostatic intraepithelial neoplasia on biopsy and architectural pattern of prostatic intraepithelial neoplasia. CONCLUSIONS: These results indicate that the presence of high grade prostatic intraepithelial neoplasia on needle biopsy is strongly predictive of carcinoma. Prostatic intraepithelial neoplasia should be reported in needle biopsies and biopsy repeated. These finding support the hypothesis that prostatic intraepithelial neoplasia is a precursor of prostate cancer.

Adenocarcinoma↗

PubMed2001

High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy.

With high-grade prostatic intraepithelial neoplasia with adjacent small atypical glands (PINATYP), the issue is whether the small glands represent budding or tangentially sectioned glands off of adjacent high-grade prostatic intraepithelial neoplasia (PIN) or invasive cancer next to high-grade PIN. The histology and significance of PINATYP on biopsy have not been described. Among 574 cases of high-grade PIN lesions on needle biopsy, we identified 71 cases of PINATYP. Most cases were consultations, and 51 cases were available for histologic review. At least 1 follow-up prostate biopsy was performed in each of 55 cases. Immunohistochemistry for high-molecular-weight cytokeratin (HMWCK) was performed on cases in which material was available. The average patient age at diagnosis was 65.5 years (range, 48 to 103 years). The initial digital rectal examination, transrectal ultrasound, serum prostate-specific antigen (PSA) level, PSA velocity, and family history of prostate cancer did not predict cancer on repeat biopsy. In 39% of cases, high-grade PIN had a predominantly flat pattern, and remaining cases showed a predominance of other patterns (tufting, micropapillary, cribriform). The average number of high-grade PIN glands and adjacent small atypical glands were 11.5 (1 to 60) and 5.3 (1 to 21), respectively. The farthest adjacent small atypical gland averaged 0.12 mm from the high-grade PIN (0.01 mm to 0.4 mm), as measured with an ocular micrometer. The following histologic features did not predict cancer on repeat biopsy: more than 1 core involved by the high-grade PIN; number of high-grade PIN glands; number of small atypical glands; distance of small atypical glands from the high-grade PIN; size and percentage of nucleoli; marked nuclear pleomorphism; and mitoses. Overall, the risk of cancer on repeat biopsy was 46%. Two findings predicted a lower risk of cancer on repeat biopsy: younger age (62.2 years benign v 68.3 years cancer; P =.004) and predominantly flat high-grade PIN (P =.007). In our material, PINATYP appears to be a greater risk factor than high-grade PIN alone in predicting cancer on rebiopsy. Although age and predominant pattern of associated high-grade PIN may be helpful in predicting which men with this lesion will have cancer on rebiopsy, they cannot be used reliably; therefore, all men with PINATYP should undergo repeat biopsy. HUM PATHOL 32:389-395.

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PubMed2005

Drug therapies for eradicating high-grade prostatic intraepithelial neoplasia in the prevention of prostate cancer.

High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor to invasive prostate cancer observed as an isolated entity in a growing subset of men undergoing prostate biopsy. The presence of HGPIN predicts an increased risk of 1) coexisting occult prostate cancer at baseline and 2) delayed progression to prostate cancer. As such, men with HGPIN represent a population at high risk for the development of prostate cancer. Because the current recommended therapy is observation and delayed-interval biopsies until cancer develops, a well-tolerated therapeutic agent capable of interrupting the progression of HGPIN to cancer is highly desirable. Given the known cancer-stimulatory effects of estrogens in the prostate, the use of selective estrogen receptor modulators (SERMs) to provide an antiestrogen effect represents a novel strategy for prostate cancer prevention. Recent phase II data from trials using toremifene in the treatment of men with HGPIN validate the use of SERMs as a rational and provocative strategy for the prevention of prostate cancer.

Journal Article↗

PubMed2001

High-grade prostate intraepithelial neoplasia shares cytogenetic alterations with invasive prostate cancer.

BACKGROUND: High-grade prostate intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma. However, the relationship between this lesion and prostate cancer has not yet been established. The detection of cytogenetic changes in the lesions prior to prostate adenocarcinoma would be useful in demonstrating such a pathogenic relationship. METHODS: Twenty eight high-grade PIN cases were found among 57 specimens of radical prostatectomy performed for clinically localized prostate cancer. Fluorescence in situ hybridization (FISH) analysis using centromeric probes to enumerate chromosomes 7, 8, 10, and 12 was performed to study the numerical chromosome alterations. FISH analysis was carried out over isolated nuclei obtained from high-grade PIN areas and prostate cancer foci in the same prostatectomy specimen. RESULTS: Of the 28 suitable cases it was possible to complete the study in 26 tumor and 20 PIN areas. The remaining cases were excluded because of insufficient tissue or poor preservation. Cytogenetic alterations (aneuploidy) were found in 16 of the 26 (62%) tumors studied. The most frequent chromosome alteration was trisomy 7, detected in 12 (75%) aneuploid tumors, followed by monosomy 8 present in 5 (31%) aneuploid tumors. Trisomy 7 was also the most frequent isolated chromosome alteration since it was detected in 7 (44%) tumors. Thirteen of 20 (65%) PIN cases were aneuploid when studied by FISH. Trisomy 7, trisomy 8, and monosomy 8 were the most common cytogenetic alterations in the 20 PIN areas studied, being observed in nine (45%), six (30%), and four (20%) cases, respectively. FISH analysis showed a high correlation (75% cases) in ploidy and pattern of cytogenetic alterations between high-grade PIN areas and the paired prostate cancer focus in the same specimen. CONCLUSIONS: The above results show a cytogenetic link between high-grade PIN and prostate cancer, suggesting that the former could be an early form of prostate cancer.

Adenocarcinoma↗

PubMed1998

Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer.

High-grade prostatic intraepithelial neoplasia (PIN) is the only widely accepted precursor lesion for prostatic adenocarcinoma (PCa). However, the spread of established PCa within prostatic ducts may be indistinguishable morphologically from high-grade PIN. By convention, all cytologically malignant cellular proliferations within prostatic ducts have been lumped into a PIN category, although there have been recent attempts by McNeal to develop reproducible criteria to separate high-grade PIN from the spread of established PCa within prostatic ducts--intraductal carcinoma (IDCa). Using McNeal's criteria for IDCa, we studied whole-mount sections from 252 patients with pT3NO PCa for the presence of IDCa and correlated the presence or absence of IDCa with Gleason score, total tumor volume, surgical margin status, seminal vesicle involvement, and disease progression. Patients with IDCa had higher Gleason score and total tumor volume and were more likely to show seminal vesicle involvement and disease progression than those patients without IDCa. In addition, IDCa was of independent prognostic significance. Total tumor volume and surgical margin status had no independent prognostic significance in this data set.

Adenocarcinoma↗

PubMed2000

[Clinical significance of prostatic intraepithelial neoplasia].

OBJECTIVE: To determine the value of high grade prostatic intraepithelial neoplasia (with or without the influence of certain risk factors) in predicting prostate cancer in subsequent biopsies. METHODS: The study comprised 41 patients from a prostate cancer screening program with high grade prostatic intraepithelial neoplasia. Subsequent biopsies were reviewed and the probability of detecting prostate cancer was calculated. We analyzed the influence of age, DRE and transrectal US findings, PSA levels and PSA density on the results of the repeat biopsies. RESULTS: The patients were aged 50 to 83 years (mean 62.8 +/- 1.6 SD, median 61). Only 27 of the 41 patients with high grade prostatic intraepithelial neoplasia accepted a repeat biopsy. Of these, prostate cancer was demonstrated in 11 (40.7%; all cases were clinically localized at the time of diagnosis) and 16 showed no changes (59.3%) on repeat biopsy. By univariate and multivariate analysis, patient age, DRE and transrectal US findings, PSA levels and PSA density were not found to be predictors of cancer in the subsequent biopsies. CONCLUSIONS: The finding of high grade prostatic intraepithelial neoplasia in the prostate biopsy carries a high probability of detecting cancer in subsequent biopsies. We therefore advocate performing a repeat biopsy in these patients.

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PubMed2003

Phase IIA clinical trial to test the efficacy and safety of Toremifene in men with high-grade prostatic intraepithelial neoplasia.

Men with high-grade prostatic intraepithelial neoplasia (PIN) evident on prostate biopsy are at high risk for the eventual development of prostate cancer. The ability to reverse high-grade PIN may reduce the incidence or delay the development of prostate cancer. Toremifene (GTx-006, Acapodene trade mark ) is a selective estrogen receptor modulator that has been shown in the transgenic mouse model of prostate cancer to eliminate high-grade PIN and reduce the incidence of prostate cancer. This study was aimed at the evaluation of the safety and efficacy of toremifene in men diagnosed with high-grade PIN. This was an open-label, phase IIA clinical trial that enrolled 21 men (mean age, 64.7 years) with evidence of high-grade PIN on biopsy within 6 months of entry into the study. Eighteen of these men (86%) completed toremifene treatment (60 mg/day orally for 4 months) and then underwent follow-up prostate biopsy (8 cores) to determine high-grade PIN status. The effect of the drug on serum prostate-specific antigen (PSA), percentage of free PSA, testosterone, estradiol, and quality of life was also measured. After toremifene treatment, 72% of these 18 men (vs. 17.9% of historical controls) had no high-grade PIN on subsequent prostate biopsies. Mean PSA trended higher, and percentage of free PSA was increased. Quality of life was not significantly affected by treatment. There were 3 mild adverse events, and no serious adverse events. Toremifene appeared to reduce high-grade PIN in this small, exploratory trial. The drug was well tolerated. A double-blind, dose-finding, randomized, placebo-controlled phase IIB/III study is currently open to further study toremifene's activity against high-grade PIN and prostate cancer incidence.

Administration, Oral↗

PubMed2004

Prostatic intraepithelial neoplasia and intestinal metaplasia in prostates of probasin-RAS transgenic mice.

BACKGROUND: Activation of the RAS pathway has been implicated in the pathogenesis of many types of human cancers, including prostate cancer. Here we employed a transgenic approach to assess the potential contribution of RAS to prostate carcinogenesis. METHODS: Probasin-RAS (Pb-RAS) transgenic mice were generated and shown to express high levels of activated RAS in the prostate lobes. Transgenic prostates were compared to normal controls by histology and immunohistochemistry with relevant markers. RESULTS: Pb-RAS transgenic prostates exhibit neoplastic changes including low-grade prostatic intraepithelial neoplasia, and metaplastic changes towards an intestinal goblet cell phenotype. The finding of high levels of the goblet cell-specific peptide Itf/Tff3 in these transgenic prostates is in accordance with recent microarray studies showing that ITF/TFF3 is upregulated in human prostate cancer samples. CONCLUSIONS: The Pb-RAS mouse model could be useful for elucidating the early events in prostate carcinogenesis, as well as for studying the mechanisms and potential prostate cancer relevance of intestinal metaplasia.

Androgen-Binding Protein↗

PubMed2000

Morphological identification of the patterns of prostatic intraepithelial neoplasia and their importance.

High grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostatic carcinoma. PIN has a high predictive value as a marker for carcinoma, and its identification in biopsy specimens warrants repeat biopsy for concurrent or subsequent carcinoma. The only methods of detection are biopsy and transurethral resection; PIN does not greatly raise the concentration of serum prostate specific antigen (PSA) or its derivatives, does not induce a palpable mass, and cannot be detected by ultrasound. Androgen deprivation decreases the prevalence and extent of PIN, suggesting that this form of treatment might play a role in chemoprevention. Radiotherapy is also associated with a decreased incidence of PIN.

Diagnosis, Differential↗

PubMed1996

Insulin-like growth factor-binding protein-2 and -3 expression in benign human prostate epithelium, prostate intraepithelial neoplasia, and adenocarcinoma of the prostate.

Insulin-like growth factor (IGF)-binding proteins (IGFBPs) modulate the activity of IGFs. In vitro human prostate epithelial cells secrete IGFBP-2 and -3. In vivo IGFBP-2 is increased, and IGFBP-3 is decreased in the serum of patients with prostate cancer. Immunohistochemistry and in situ hybridization were performed to compare the expression of IGFBP-2 and -3 in vivo in prostate tissue containing benign epithelium, high grade prostate intraepithelial neoplasia (PIN), and adenocarcinoma. Immunoreactivity and messenger ribonucleic acid (mRNA) hybridization signals for IGFBP-2 and -3 were localized to epithelial cells. IGFBP-2 immunostaining intensity was significantly increased in PIN regions compared to that in normal epithelium and was further increased in malignant cells. IGFBP-2 mRNA was also significantly increased in PIN and cancer cells. IGFBP-3 immunoreactivity was significantly increased in PIN regions compared to normal epithelium; however, IGFBP-3 protein was significantly decreased in malignant cells. IGFBP-3 mRNA remained virtually unchanged in benign epithelium, PIN, and adenocarcinoma cells. These results demonstrate that increased IGFBP-2 protein in PIN and malignant cells is probably due to increased mRNA expression. However, levels of IGFBP-3 protein may be due to pre- and/or posttranslational mechanisms, including proteolysis. The changes in IGFBP-2 and -3 protein levels in prostatic tissue are in agreement with serum changes reported in patients with prostate cancer.

Adenocarcinoma↗

PubMed1996

Androgen receptor expression in prostatic dysplasia (prostatic intraepithelial neoplasia) in the human prostate: an immunohistochemical and in situ hybridization study.

To evaluate the role of androgens in the pathogenesis of prostatic dysplasia, we compared the localization of androgen receptor (AR) in proliferative and nonproliferative cells in normal and dysplastic acini. Basal cells, the only proliferating cells identified in normal acini, contained AR mRNA but lacked an immunodetectable receptor. Both AR mRNA and immunodetectable receptor were present, however, in secretory and stromal cells. Androgen receptor localization in dysplastic lesions was identical to normal but here the proliferative marker Ki-67 was found in both basal and secretory cells. Our findings suggest that androgens do not directly initiate the division of basal cells, the putative precursors of secretory cells. Instead, the hormone may act through its fully translated receptor to mainly mediate the differentiation of secretory cells. The presence of both AR and Ki-67 in dysplastic secretory cells may indicate an abnormal direct androgen-mediated proliferation in this compartment. This is consistent with previous evidence that secretory cell differentiation is impaired in dysplasia.

Aged↗

PubMed1997

Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker.

OBJECTIVES: We describe the expression of a potentially new tumor marker, human glandular kallikrein 2 (hK2), that may be useful as an adjunct to prostate-specific antigen (PSA) in the diagnosis and monitoring of prostate cancer. METHODS: We evaluated 257 radical prostatectomy specimens removed at the Mayo Clinic with pathologic Stage 12 adenocarcinoma to compare the cytoplasmic expression of hK2, PSA, and prostatic acid phosphatase (PAP) in benign tissue, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. Two monoclonal antibodies, hK2-A523 and hK2-G586, specific for hK2 were used, as well as antibodies against PSA (PSM-773) and PAP (polyclonal). RESULTS: Intense epithelial cytoplasmic immunoreactivity was observed in every case for hK2-A523, hK2-G586, PSA, and PAP (100% of cases, respectively). The intensity and extent of hK2 expression for both antibodies were greater in cancer than high-grade PIN; furthermore, high-grade PIN was greater than benign epithelium. Cases of Gleason primary grade 4 and 5 cancer showed hK2 staining in almost every cell, whereas there was greater heterogeneity of staining in lower grades of cancer. In marked contrast to hK2, PSA and PAP immunoreactivity was most intense in benign epithelium and stained to a lesser extent in PIN and carcinoma. The number of immunoreactive cells for hK2 and PSA was not predictive of cancer recurrence. CONCLUSIONS: hK2 was expressed in every cancer, and the expression incrementally increased from benign epithelium to high-grade PIN and adenocarcinoma. PSA and PAP displayed inverse immunoreactivity compared with hK2. The expression of hK2 and PSA was not predictive of cancer recurrence in patients with Stage T2 carcinoma. Expression of hK2 indicates that this kallikrein antigen is both prostate localized and tumor associated. Tissue expression of hK2 appears to be regulated independently of PSA and PAP. Further studies are needed to determine whether tissue immunoreactivity of hK2 will prove clinically useful in the diagnosis and monitoring of prostate cancer.

Acid Phosphatase↗

PubMed1999

Effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia and its prognostic significance.

PURPOSE: We studied the effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia in patients undergoing radical prostatectomy and assessed the effect of prostatic intraepithelial neoplasia on disease recurrence as measured by serum prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 278 patients with clinically localized prostate cancer were included in phase II and III studies evaluating radical prostatectomy alone versus radical prostatectomy following neoadjuvant hormonal therapy at Memorial Sloan-Kettering Cancer Center between October 1991 and August 1996. Patient data related to prostatic intraepithelial neoplasia were analyzed. RESULTS: Of 275 evaluable patients 145 (52.7%) had prostatic intraepithelial neoplasia. Of 50 patients treated with neoadjuvant hormonal therapy (hormone group) 22 (44%) had a lower incidence of prostatic intraepithelial neoplasia compared to 69 of 80 controls (86.3%) (chi-square test p<0.0001). Of 262 patients (95.3%) with followup PSA 44 (16.8%) had PSA recurrence at a median followup of 32 months, with a median time to recurrence of 30 months. PSA recurrence was noted in 23 of 145 patients with compared to 21 of 130 without prostatic intraepithelial neoplasia (chi-square test p = 0.95), and did not significantly differ between the hormone group (25 of 142, 17.6%) and controls (19 of 130, 14.6%) (chi-square test p = 0.45). CONCLUSIONS: While patients treated with neoadjuvant hormonal therapy had significantly lower incidence of prostatic intraepithelial neoplasia, neither prostatic intraepithelial neoplasia nor neoadjuvant hormonal therapy significantly affected PSA recurrence at a median followup of 32 months.

Antineoplastic Agents, Hormonal↗

PubMed2006

Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia.

Typically glands of prostatic adenocarcinoma have a single cell lining, although stratification can be seen in invasive carcinomas with a cribriform architecture, including ductal carcinoma. The presence and diagnostic significance of stratified cells within non-cribriform carcinomatous prostatic glands has not been well addressed. The histomorphological features and immunohistochemical profile of cases of non-cribriform prostatic adenocarcinoma with stratified malignant glandular epithelium were analyzed. These cases were identified from needle biopsy cases from the consultation files of one of the authors and from a review of 150 consecutive in-house needle biopsy cases of prostatic adenocarcinoma. Immunohistochemistry was performed utilizing antibodies reactive against high molecular weight cytokeratin (34betaE12), p63 and alpha-methylacyl-coenzyme-A racemase (AMACR). A total of 8 cases were identified, including 2 from the 150 consecutive in-house cases (1.3%). In 4 cases, the focus with glands having stratified epithelium was the sole carcinomatous component in the biopsy, while such a component represented 5-30% of the invasive carcinoma seen elsewhere in the remaining cases. The main attribute in all these foci was the presence of glandular profiles lined by several layers of epithelial cells with cytological and architectural features resembling flat or tufted high-grade prostatic intraepithelial neoplasia, but lacking basal cells as confirmed by negative 34betaE12 and/or p63 immunostains in all cases. The AMACR staining profile of the stratified foci was variable, with 4 foci showing positivity, and 3 foci being negative, including two cases that displayed AMACR positivity in adjacent non-stratified prostatic adenocarcinoma. Prostatic adenocarcinoma with stratified malignant glandular epithelium can be identified in prostate needle biopsy samples harboring non-cribriform prostatic adenocarcinoma and resembles glands with high-grade prostatic intraepithelial neoplasia. These 'PIN-like' carcinomas can present in pure form. Recognition of this pattern of prostatic adenocarcinoma is necessary to correctly diagnose such cases as invasive carcinoma.

Adenocarcinoma↗

PubMed1996

Numerical chromosomal changes in high-grade prostatic intraepithelial neoplasia (PIN) and concomitant invasive carcinoma.

Prostatic intraepithelial neoplasia (PIN) is regarded as a precursor lesion of at least some prostatic cancers. Using interphase cytogenetics, an in situ hybridization technique with chromosome specific probes, we investigated 15 prostatectomy specimens containing both invasive carcinoma and PIN for the presence of numerical changes of chromosomes 7, 8, 10, 17 and X. The results were correlated with tumor stage and Gleason grade as well as with morphological features of PIN. Of the 15 carcinomas, four were disomic, five displayed at least focal chromosomal gains and six were found to be aneusomic. A non-disomic chromosomal status correlated well with a higher tumor stage and grade. Although the majority of PIN glands showed an eusomy, focal chromosomal gains within single glands or parts of a gland could be observed in 12 of the 15 cases. All but one specimen with non-disomic carcinomas also harboured areas of PIN with numerical chromosomal aberrations, often laying directly adjacent to tumorous glands. Additionally, focal non-disomies of PIN could also be detected in two cases with eusomic cancer. With regard to numerical changes in PIN and cancer, no significant preponderance could be observed for the five chromosomes tested. We conclude that numerical chromosomal aberrations are a frequent, but mostly focal event in PIN. This karyotypic instability is further evidence for the premalignant nature of this lesion.

Adenocarcinoma↗

PubMed2005

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

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

Aged↗