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PubMed2000

Effect of high-grade prostatic intraepithelial neoplasia on total and percent free serum prostatic-specific antigen.

OBJECTIVE: To analyze the influence of high-grade prostatic intraepithelial neoplasia (HGPIN) on total serum prostatic-specific antigen (PSA) and percent free PSA. METHODS: Total and free serum PSA were determined in 81 consecutive patients with clinical T1c prostate cancer who underwent radical prostatectomy. HGPIN was detected in 62 specimens (76.5%). RESULTS: Median total PSA was 9.2 ng/ml when there was not HGPIN and 8.1 ng/ml when it existed, p>0.05. Median percent free PSA was 11.7 and 9.1%, respectively, p<0.03. However, a multiple linear regression analysis demonstrated there was no effect of HGPIN on total PSA nor on percent free PSA. Percent free serum PSA was significantly influenced by total PSA and the pathological tumor stage. CONCLUSION: HGPIN does not seem to contribute significantly on serum total PSA and percent free PSA.

Adult↗
PubMed1996

Prostatic intraepithelial neoplasia does not appear to raise serum prostate-specific antigen concentration.

OBJECTIVES: Conflicting findings have been reported regarding the relationship between prostatic intraepithelial neoplasia (PIN) and serum prostate-specific antigen (PSA) concentration. This study evaluates whether high-grade PIN significantly raises serum PSA concentration. METHODS: We evaluated 194 totally embedded whole-mounted radical prostatectomy specimens removed for clinically localized prostate cancer. No patient received preoperative therapy. In each specimen, the volume of high-grade PIN and carcinoma was calculated using the grid-counting method. Serum PSA concentration was determined prior to surgery. Cancer volume, gland weight, Gleason score, extraprostatic extension, and PIN volume were then compared according to serum PSA concentration and PSA density. RESULTS: Of the 194 patients, 170 (88%) had high-grade PIN-associated cancer and 24 (12%) had PIN-free cancer within the specimen. PIN volume ranged from 0 to 8.1 cc (mean, 1.3) and cancer volume ranged from 0 to 56.9 cc (mean, 9.1). In a subset of 93 patients with small cancers (less than 6.0 cc), PIN volume ranged from 0 to 6.1 (mean, 0.83) and did not correlate with serum PSA concentration or PSA density (P = 0.80 and P = 0.69, respectively). In the entire study group, PIN volume did not correlate with PSA density (P = 0.17), but did correlate with serum PSA concentration (P = 0.005). Using multiple regression analysis, adjusting for cancer volume, gland weight, Gleason score, and extraprostatic extension, log PIN volume did not contribute to log serum PSA concentration (regression coefficient -0.108; P = 0.51) or log PSA density (regression coefficient -0.104; P = 0.56) in small cancers (less than 6.0 cc). In the entire study group, log PIN volume did not contribute to log serum PSA concentration (regression coefficient -0.182; P = 0.05) or log PSA density (regression coefficient -0.202; P = 0.56). CONCLUSIONS: Our data indicate that high-grade PIN does not significantly contribute to serum PSA concentration. We suggest that patients with elevated serum PSA concentration found to have high-grade PIN on transrectal biopsy should not have their elevated serum PSA concentration attributed to high-grade PIN.

Aged↗
PubMed2006

Allelotyping analysis at chromosome arm 8p of high-grade prostatic intraepithelial neoplasia and incidental, latent, and clinical prostate cancers.

In this study, we used 7 informative microsatellite markers at 8p22, 23.1, and 23.2 in Japanese patients to compare frequency of loss of heterozygosity (LOH) in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC), 31 cases (41 lesions) of latent prostate cancer (LPC), and 102 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 8p22-23.2 with at least 1 marker was 0%, 33%, 57%, and 51% in the HGPIN, IPC, LPC, and CPC cases, respectively. No statistically significant difference was found at 8p22-23.2 between the types of prostate cancer. However, the frequency of 8p22 deletion was significantly higher in CPC and LPC cases than in IPC cases (P = 0.0003) or lesions (P = 0.0017). The frequency of LOH at 8p22 and 8p23.1 loci in high-grade tumors was significantly higher than in low-grade tumors in both the LPCs/IPCs and CPCs (P < 0.05). Allelic loss at 8p22 was significantly more frequent in CPC than in IPC (P = 0.002) and in pT4 CPC than in earlier-stage CPC (P = 0.038). These findings suggest that deletion of 8p is an important event in both the initiation and metastasis of prostate cancer. The extremely high frequency of LOH at 8p22-23.1 in high-grade tumors suggests the existence of a novel putative tumor-suppressor gene associated with the progression of prostate cancer. These results should be useful in identifying the target gene of deletion at 8p.

Alleles↗
PubMed1998

Digital image analysis of proliferative index: two distinct populations of high-grade prostatic intraepithelial neoplasia in close proximity to adenocarcinoma of the prostate.

A considerable amount of data has been collected showing the association of high-grade prostatic intraepithelial neoplasia (HGPIN) with adenocarcinoma of the prostate, and many studies have yielded results that suggest that HGPIN is a precursor of carcinoma. A few studies have indicated that HGPIN may, in some cases, be a sequela of prostatic adenocarcinoma. We examined the proliferative indices of HGPIN, carcinoma, and benign prostatic epithelium by computer-aided counting of Ki-67-positive nuclei in 15 cases in which HGPIN and carcinoma were in close proximity. There were 13 radical prostatectomy specimens with prostate cancer and two cystoprostatectomy specimens with both transitional cell carcinoma and prostatic adenocarcinoma. First, we showed the accuracy of the computer-aided counting method compared with direct counting through the binoculars of the microscope. Then proliferative activity was assessed for each case by picking the two areas of carcinoma, the two areas of HGPIN, and the one area of benign epithelium with the greatest density of carcinomatous, dysplastic, and benign Ki-67-positive nuclei, respectively. The total number of nuclei and the number of positive nuclei were counted. Basal cells were not counted. The mean proliferative index was higher for cancer (caindex, average 0.054) than for HGPIN (pinindex, average 0.048) (P < .05). We found that the 15 cases fell into two distinct groups. The average ratio of pinindex to caindex (pinindex/caindex) was lower in group 1 (0.72) than in group 2 (1.54) (P=.17), and when the results were corrected for the nonzero gamma-intercepts of the regression lines of pinindex versus caindex, the ranges were widely separated, and the difference between the means was statistically significant (0.15 v 0.62; P < .0001). A greater subjective similarity between the nuclear features in the HGPIN and those of the corresponding carcinoma was noted for the cases in group 2. The average value of bngnindx was 0.014. The value of bngnindx did not correlate with either caindex or pinindex. We conclude that there may be two types of lesions with the morphological appearance of HGPIN and that they may have different relationships to carcinoma. Computer-aided counting of digitized microscopic images is both labor-saving and as accurate as enumeration directly through the binoculars of the microscope.

Adenocarcinoma↗
PubMed1999

Progression-linked overexpression of c-Met in prostatic intraepithelial neoplasia and latent as well as clinical prostate cancers.

The c-met proto-oncogene encoding the receptor for the hepatocyte growth factor is expressed in several cancers. In the present study, c-met protein (c-Met) was detected in eight of 22 (36%) cases of prostatic intraepithelial neoplasia (PIN), five of 15 (33%) latent and 17 of 21 (81%) clinical prostate cancers, including seven metastatic lesions, using an immunohistochemical method. All seven (100%) metastatic lesions investigated demonstrated strong staining, and a correlation between c-Met expression and histology was observed. These results suggest a significant relationship between c-Met expression and progression of prostate neoplasms, including latent cancers.

Adenocarcinoma↗
PubMed2004

Nuclear factor-kappaB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate.

PURPOSE: The transcription factor nuclear factor-kappaB (NF-kappaB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis. EXPERIMENTAL DESIGN: Electromobility gel shift assays were used to evaluate NF-kappaB DNA binding in vitro. The functional relevance of NF-kappaB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-kappaB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-kappaB subunit was used to determine the frequency and location of NF-kappaB in 97 prostatectomy specimens. The amount of staining was quantified on a 0-3+ scale. RESULTS: An electromobility gel shift assay confirmed the presence of NFkappaB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-kappaB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage. CONCLUSIONS: NF-kappaB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-kappaB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-kappaB for the prevention and/or treatment of prostate cancer.

Adenocarcinoma↗
PubMed1995

Prostatic intraepithelial neoplasia: a potential precursor lesion of prostatic adenocarcinoma.

The necessity of early detection of prostate cancer renewed interest regarding putative premalignant lesions in the tumorigenesis of the prostate. Prostatic intraepithelial neoplasia (PIN) is one potential precursor for prostatic adenocarcinoma. The term PIN has been adopted to replace a wide range of synonyms in the literature that describe potential precursors. PIN is an intraluminal proliferation of the secretory cells lining architecturally benign prostatic ducts and acini that exhibit cytologic atypia. In this review, we discuss the histologic features, the differential diagnosis, the evidence that PIN is a precursor of prostatic carcinoma, and the clinical significance of PIN.

Adenocarcinoma↗
PubMed1996

Chemoprevention for prostatic intraepithelial neoplasia.

OBJECTIVES: To evaluate the potential application of chemoprevention strategies in prostatic intraepithelial neoplasia. METHODS: Review of relevant literature on chemoprevention with emphasis on prostate cancer and premalignant lesions. RESULTS: Chemoprevention represents a strategy designed to inhibit or reverse the process of carcinogenesis by administering one or several noncytotoxic chemical compounds. The epidemiology of prostate carcinoma indicates that this cancer is a prime candidate for a strategy aimed at prevention due to the extremely high prevalence rate, rising annual incidence, and long latent interval between the cancer-initiating events and the development of invasive disease. Chemopreventive agents may exert their inhibitory effects at different stages of the multistep carcinogenic process broadly categorized as initiation, promotion, and progression. The synthetic retinoids, polyamine synthesis inhibitors, and antiandrogens are among the compounds shown to have in vitro or in vivo chemopreventive effects in prostate carcinogenesis. A major limitation in the evaluation of such agents in a human prostate cancer is the long duration of clinical trials required to assess the efficacy with an endpoint of cancer development. Premalignant epithelial changes such as prostate intraepithelial neoplasia, or PIN, are highly associated with prostate cancer, and share many molecular features of invasive cancer. If the reversal or inhibition of intraepithelial neoplasia translates to a concomitant reduction in clinically relevant prostate cancer, then the pharmacological modulation of PIN may provide a rapid means to evaluate the effects and benefits of potential chemopreventive agents. CONCLUSION: Men with PIN may represent ideal candidates for chemoprevention protocols. The ideal agent and duration of therapy remains to be defined.

Androgen Antagonists↗
PubMed1995

Nucleolar and AgNOR-analysis of prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia (AAH) and prostatic carcinoma.

Atypical glandular proliferations of the prostate are found in combination with prostate carcinomas but also with benign prostatic hyperplasia (BPH). These atypical glandular lesions that mimic glandular carcinoma within the anterocentral part of the prostate (transition zone) are named "atypical adenomatous hyperplasia (AAH)." The term for atypical ductal and acinar mainly papillary and/or cribriform proliferations in the peripheral zone is "prostatic intraepithelial neoplasia (PIN)." In this study the significance of the status of nucleoli and the number of silver-stained nucleolar organizing regions (AgNOR) as a method for measuring proliferative activity was investigated in biopsies of AAH, PIN and carcinomas of different grades of malignancy. The aim was to prove whether there are relationships of AAH to low grade carcinomas on the one hand and of PIN to high grade carcinomas on the other hand. The frequency of nuclei with small nucleoli was low in BPH (0.6%). The values increased to 8.3% in AAH, and 28.7% in PIN. The frequency of nuclei with prominent nucleoli in low grade carcinomas was 41.7% and in high grade carcinomas 81.1%. Usually, one single nucleolus was found per nucleus. Multiple prominent nucleoli were found in high grade carcinomas and in some cases of high grade PIN only. The result of AgNOR-analysis was similar: low numbers in BPH, low to moderate values in AAH, moderate values in low grade carcinomas and high values in PIN, as well as high grade carcinomas. Besides correlation between topography, histology and cytology, the similarities of nucleolar and AgNOR-analysis between PIN and high grade carcinomas support the idea that PIN is the precursor of the peripheral prostatic carcinoma. The histological, cytological and cell kinetical features of AAH are intermediate between BPH and low grade carcinoma of the prostate. Therefore, the findings to date are inconclusive and further follow up studies are necessary to prove if AAH may be a precursor of transition zone carcinoma of the prostate.

Adenocarcinoma↗
PubMed1992

Aneuploidy and nuclear features of prostatic intraepithelial neoplasia (PIN).

Quantitative analyses (QAs) of prostatic intraepithelial neoplasia (PIN) helped to objectively define some traditional features of the lesion because, first, changes in value are represented by numbers and not by subjective evaluation of morphologic clues. QAs have also helped to identify subtle abnormalities. For example, the degree of nucleolar margination is a new diagnostic feature which can be easily evaluated as the proportion of nucleoli touching the nuclear membrane. Thirdly, QAs have provided useful insights into understanding some morphologic changes. PIN, in fact, appears to be characterized by complex changes which involve the secretory cells as well as the basal layer and which affect the surrounding stroma. In the epithelial lining, two types of simultaneous changes take place, the first in the nucleus (expression of abnormal proliferative and/or renewal activity) and the second in the cytoplasm (expression of the disorder in cell differentiation), pointing out that only PIN samples of high grade can be considered as having acquired the characteristics of a neoplastic lesion.

Aneuploidy↗
PubMed1998

Different patterns of p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of microdissected specimens.

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and can be divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic carcinoma (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 29 cases of PCA and 1 benign prostatic hypertrophy were analyzed for p53 mutation by single-strand conformation polymorphism (SSCP) of polymerase chain reaction (PCR)-amplified DNA fragments followed by direct sequencing. These patients had received total prostatectomy (27 cases) or transurethral resection (3 cases). Under direct microscopic observation, DNA was microdissected from 108 lesions: 67 lesions from 22 cases of PIN (55 HGPIN and 12 LGPIN), 29 from 22 cases of PCA, and 12 from 11 cases of adjoining benign glands. Analysis revealed 13 mutations in 10 lesions from six cases. All 13 were point mutations: 7 missense, 5 silent, and 1 nonsense. Mutations were detected in 3 cases (14%) of PIN and 5 cases (25%) of PCA. PIN lesions with p53 mutations were all categorized as HGPIN. Neither LGPIN nor benign glands adjoining PIN and/or PCA had mutations. Two PIN and one PCA lesion in each of two cases had mutations that were different from each other. G-to-A transition was the commonest mutation pattern. The current findings showed that HGPIN, but not LGPIN, and PCA are similar with regard to p53 mutation. The diverse patterns of p53 mutation among HGPIN and PCA lesions suggested multiclonal development of prostatic precancerous lesions.

Amino Acid Substitution↗
PubMed1997

[Relationship of prostatic carcinoma of the peripheral zone with glandular atrophy and prostatic intraepithelial neoplasia].

The study of the prostate's peripheral area in 32 patients, with age ranging between 48 to 75 years (mean, 61.4 +/- 6.7), demonstrates the frequency of certain morphological changes such as glandular atrophy (46.8%), which are neither related to age (p = 0.8) or the carcinoma (p = 0.8). A very different issue is the prostatic intraepithelial neoplasia, which although not statistically related to age in this series (p = 0.3) (probably due to the absence of young adults), appears to develop in earlier stages than cancer, is associated in 88.8% carcinomas (p = 0.03) and has a close topographic correlation to latent microscopic foci of adenocarcinoma of the prostate's peripheral area, anatomic proximity of both lesions occurring in 55.5% cases.

Adenocarcinoma↗
PubMed2003

High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia.

EphA2 is a transmembrane receptor tyrosine kinase that is overexpressed in many carcinomas. Specific targeting of EphA2 with monoclonal antibodies is sufficient to inhibit the growth, migration and invasiveness of aggressive cancers in animal models. Using immunohistochemical analyses, we measured the expression of EphA2 in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostate tissue from ninety-three radical prostatectomy specimens. These results were related to multiple clinical and pathologicalcharacteristics. The fraction of cells staining positively with EphA2 in benign prostatic epithelium (mean, 12%) was significantly lower than that in high-grade prostatic intraepithelial neoplasia (mean, 67%, P < 0.001) and prostatic adenocarcinoma (mean, 85%, P < 0.001). Moreover, the intensity of EphA2 immunoreactivity in prostatic adenocarcinoma was significantly higher than in benign prostatic tissue (P < 0.001) or high-grade prostatic intraepithelial neoplasia (P < 0.001). Benign prostatic epithelium showed weak or no immunoreactivity for EphA2 in all cases examined. Whereas EphA2 immunoreactivity related to neoplastic transformation, it did not correlate with other clinical and pathological parameters examined. Our data suggest that EphA2 levels increase as prostatic epithelial cells progress toward a more aggressive phenotype. Progressively higher levels of EphA2 in high-grade prostatic intraepithelial neoplasia and prostatic carcinoma are consistent with recent evidence that EphA2 functions as a powerful oncogene. Moreover, the presence of high levels of EphA2 in these cells suggests opportunities for prostate cancer prevention and treatment.

Adenocarcinoma↗
PubMed2004

[Expression and significance of activated leukocyte cell adhesion molecule in prostatic intraepithelial neoplasia and adenocarcinoma].

OBJECTIVE: To investigate the expression of activated leukocyte cell adhesion molecule(ALCAM) protein in prostatic intraepithelial neoplasia and adenocarcinoma, and the relationship between ALCAM expression and clinicopathological features of prostatic carcinoma. METHODS: ALCAM protein expression was evaluated in the tissues of 41 human prostatic carcinomas by using immunohistochemistry (EnVision method). RESULTS: ALCAM was widely expressed in prostatic epithelia. Overexpression of ALCAM was found in most prostatic intraepithelial neoplasias and low-grade cancers, whereas a decreased expression shown in some high-grade cancers. The ALCAM protein expression in prostatic carcinoma was correlated with pathological grading. However, no correlation of ALCAM expression was found with preoperative serum prostate-specific antigen levels or clinical stages. CONCLUSION: Expression of ALCAM is disturbed in prostatic intraepithelial neoplasia and adenocarcinoma, indicating its involvement in the development of human prostatic carcinoma.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1997

Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens.

OBJECTIVES: High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of invasive prostatic adenocarcinoma. The incidence and clinical significance of this lesion have not been previously defined in specimens from transurethral resections of the prostate (TURP). METHODS: To determine the frequency of PIN in TURP specimens and its relationship with adenocarcinoma, we reviewed 698 resections performed at Mayo Clinic between 1989 and 1990. A mean of 6 slides was analyzed for each case (range 1 to 36). The presence, extent, and architectural pattern of PIN were recorded. The results were correlated with many clinical and pathologic features, including patient age, Gleason score, stage, serum prostate-specific antigen (PSA) concentration, and patient follow-up. In a 1:2 nested matching case-control study, we compared the outcome of cases with PIN alone with that of the control group. Each patient with PIN alone (16 patients) was matched randomly with 2 patients with benign prostatic hyperplasia (BPH) alone (32 patients) according to age (+/- 5 years) and serum PSA concentration (+/- 1 ng/mL). RESULTS: Of 698 TURP specimens, 570 (81.7%) contained BPH and 128 (18.3%) contained adenocarcinoma and BPH. High-grade PIN was identified in 29 cases (4.2%), including 16 (2.8%) of those with BPH and 13 (10.2%) of those with cancer and BPH. Follow-up revealed adenocarcinoma in 3 of 14 patients (21.4%) with PIN and BPH only after 3, 5, and 7 years, respectively; mean follow-up for the 14 patients was 6 years (range 4 to 7 years), and none of the patients died of prostate cancer. Conversely, none of the patients (0%) without PIN in TURP specimens in the case-control study had subsequent adenocarcinoma. CONCLUSIONS: The overall incidence of PIN in TURP specimens was 4.2%, including 2.8% without cancer and 10.2% with coexistent cancer. Prostatic adenocarcinoma was diagnosed within 7 years in 21.4% of patients with PIN in TURP specimen. Conversely, none of those without PIN matched for age and serum PSA had adenocarcinoma at follow-up. These results indicate that high-grade PIN is uncommon in TURP specimens and, when found, indicates a significant risk of cancer. The presence of PIN in TURP specimens should be reported by the pathologist; in addition, the entire specimen should be submitted for histologic examination to exclude carcinoma.

Adenocarcinoma↗
PubMed1997

Allelic loss of 8p sequences in prostatic intraepithelial neoplasia and carcinoma.

OBJECTIVES: Previous work has suggested that prostatic intraepithelial neoplasia (PIN) may be a premalignant lesion important in tumorigenesis of the prostate. However, to adequately test this hypothesis at the genetic level, it is necessary to determine whether lesions in close proximity demonstrate similar genetic alterations and, hence, whether an "evolutionary" relationship might exist between PIN and tumor in the same prostate. Therefore, the purpose of this study was to examine at least two PIN lesions per prostate (one adjacent to and another distant from malignant lesions in the same prostate) for similarities or differences in the types and frequencies of genetic alterations. METHODS: To accomplish this goal, DNA was extracted from microdissected PIN, tumor, and normal epithelial tissue samples from 48 radical prostatectomies and amplified using polymerase chain reaction techniques at highly polymorphic microsatellite repeat sequences at proximal (D8S87, 8p12) and distal (NEFL, 8p21) loci on the short arm of chromosome 8. PIN specimens were either adjacent to (within one high-power microscopic field [HPF]) or distant from (separated by two or more HPFs) tumor specimens from the same patients. RESULTS: Similar fractional allelic loss frequencies were observed for informative tumor (10 [35%] of 29) and PIN (6 [21%] of 29) samples at the NEFL locus, but allelic loss at the D8S87 locus was observed only in tumors (8 [22%] of 36 informative samples). Moreover, allelic loss at the NEFL locus involved the same allele in 4 cases and different alleles in 3 cases. Interestingly, all 4 cases with the same allele loss were from adjacent PIN and tumor tissues, and all 3 with different allele loss were from distant PIN and tumor. CONCLUSIONS: These results suggest that PIN and invasive cancer share common genetic events (eg, deletion at the NEFL locus) along the same pathway of development in the prostrate.

DNA, Neoplasm↗