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PubMed2001

Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens.

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutations of the Fas gene might be involved in proliferative diseases of the prostate by prolongation of programmed cell death of prostatic epithelial cells. Using the laser capture microdissection method, Fas gene mutations were examined on genomic DNA extracted from lesions with high-grade prostatic intraepithelial neoplasia (HGPIN), a possible precursor of prostatic cancer (PCA), and from PCA. A total of 193 lesions, 111 with HGPIN, 55 with PCA, and 27 benign glands, were microdissected from 27 patients with PCA. Polymerase chain reaction-amplified products were directly sequenced. Loss of heterozygosity (LOH) was examined at four sites of known polymorphisms. Fas gene mutations were detected in HGPIN: 4 of 27 (14.8%) cases or 4 of 111 (3.6%) lesions. All were point mutations: three missense and one nonsense in the death domain. Benign proliferative glands adjoining HGPIN and/or PCA, and PCA never showed mutations. LOH was found in 31.3% of PCA and 25% of HGPIN lesions, but was never found in benign glands. Exclusive occurrence of Fas mutations in HGPIN might underlie the development of these lesions. Occasional findings of LOH in HGPIN and PCA suggested that genetic instability might occur during the early phase of prostatic carcinogenesis.

Alleles↗
PubMed1995

Prostatic intraepithelial neoplasia. Quantitation of the basal cell layer with machine vision system.

The aim of this paper is to report on a fully automated procedure to quantify the epithelial cell components in prostatic intraepithelial neoplasia with particular emphasis on the basal cell layer (BCL). Scene segmentation was guided by a knowledge-based system of digitized images recorded from histological section immunostained against high molecular weight keratin and counterstained with hematoxylin and eosin. Scene segmentation involved two major stages. First, the system located and identified the duct and segmented the scene, resulting in "intermediate segmentation products." This stage was followed by a reconstruction process in which the segmentation products (i.e., the lumen and the darkly and lightly stained epithelial cell components) were assembled to form the microscopic structure to achieve working unity. Following this, histometric measurements were made of the reconstructed scene. Computed were the percentage of the duct contour with BCL (90%), and the number and length of gaps in the BCL (19, ranging from 10 to 90 microns). Automated analysis of the BCL is accurate and provides information not readily identified by human examination.

Basement Membrane↗
PubMed1996

Immunolocalization of glycoprotein A-80 in prostatic carcinoma and prostatic intraepithelial neoplasia.

A-80 is a mucin-like glycoprotein associated with exocrine differentiation that shows little or no expression in normal exocrine cells and typical adenomas, but is upregulated in dysplasia and adenocarcinoma of certain organs. Its expression has not been systematically examined in prostatic adenocarcinoma and its putative precursor, prostatic intraepithelial neoplasia (PIN). The authors applied a mouse monoclonal antibody against A-80 in paraffin-embedded sections from 103 cases of prostatic carcinoma, 26 cases of nodular hyperplasia, 7 autopsy samples from normal young adult prostates, and 12 fetal prostates. All but one cancer reacted, although expression was heterogeneous; 75 of 103 stained extensively (> 3+ on a 0 to 5+ scale) and strongly. Staining extent and intensity were independent of tumor grade, and tended to be strong even when focal. Seventy-seven of 84 foci (92%) of high-grade PIN and 38 of 52 foci (73%) of low-grade PIN stained for A-80; reactions were most extensive and intense in high grade PIN. Only 5 of 26 cases (19%) of hyperplasia reacted, and this consisted of weak to moderate staining in sporadic cells; the remainder were negative. Normal adult prostatic epithelium did not express A-80 except for weak and inconsistent staining in foci of inflammation and infarction; atrophic glands were negative. Fetal prostate showed focally strong reactivity. These results indicate that A-80 is selectively expressed in most cases of intraepithelial neoplasia and prostate cancer, but is usually absent in benign and hyperplastic epithelium. The upregulation of glycoprotein A-80 in PIN and adenocarcinoma parallels observations in other organs, such as the breast and colon, suggesting that this is a significant oncodevelopmental molecule with potential clinical applications.

Adult↗
PubMed2006

Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice.

PURPOSE: Epidemiologic studies have shown that reduced levels of vitamin D represent a major risk factor for prostate cancer. In this report, we have examined the efficacy of 1alpha,25-dihydroxyvitamin D(3) (1,25 D(3)) as a chemopreventive agent using Nkx3.1; Pten mutant mice, which recapitulate stages of prostate carcinogenesis from prostate intraepithelial neoplasia (PIN) to adenocarcinoma. EXPERIMENTAL DESIGN: 1,25 D(3) (or vehicle) was delivered continuously to Nkx3.1; Pten mutant or control mice for a 4-month period beginning before (precancerous cohort) or after (cancerous cohort) these mice developed PIN. At the conclusion of the study, the mice were analyzed for the occurrence of PIN and/or cancer phenotypes by histologic analyses and immunostaining using known markers of cancer progression in these mice. RESULTS: We found that sustained delivery of 1,25 D(3) to the Nkx3.1; Pten mutant mice resulted in a significant reduction in the formation of PIN while having no apparent effect on the control mice. Furthermore, 1,25 D(3) was maximally effective when delivered before, rather than subsequent to, the initial occurrence of PIN. We further show that this 1,25 D(3)-mediated inhibition of PIN was coincident with up-regulation of vitamin D receptor expression in the prostatic epithelium of the mutant mice, as well as in CASP prostate epithelial cell lines developed from these mice, while having no effect on androgen receptor expression or androgen receptor signaling. CONCLUSION: Our findings show the value of chemoprevention studies using Nkx3.1; Pten mutant mice, particularly for evaluating the efficacy and underlying mechanisms of potential agents and to gain insights about the optimal timing of their delivery. In particular, our study predicts that vitamin D may have differential effects during early-stage versus late-stage disease and that it is more likely to be beneficial if delivered either before the overt manifestation of clinically detectable disease or during the earliest disease stages, rather than in advanced disease. Thus, our findings support the assessment of vitamin D analogues for chemoprevention in clinical trials targeting patients with early-stage disease and also establish molecular markers that can be used in such trials to determine biological activity and to optimize further clinical trials.

Adenocarcinoma↗
PubMed1992

Prostatic intraepithelial neoplasia (PIN): morphological clinical significance.

Premalignant lesions of the prostate fall into two categories. The first category includes formation of new, usually small, glands which are either abnormally distributed or show minimal nuclear atypia or both. Morphologically, this lesion presents the differential diagnostic alternatives of micro-acinar hyperplasia on the one hand and a low grade micro-acinar cancer on the other. If the presence or absence of nuclear anaplasia or acinar dispersion (i.e., stromal invasion) raises any degree of doubt, atypical glands are diagnosed. This is the category that is considered by some to be the precursor of well differentiated prostate cancer. The second category is prostatic intraepithelial neoplasia (PIN). We have defined PIN as an intra-acinar or ductal proliferation of secretory cells with unequivocal nuclear anaplasia, which corresponds to nuclear grade 2 and 3 invasive prostate cancer. We consider PIN as essentially carcinoma in situ. The lesion designated by some as PIN 1 is classified by us as atypical hyperplasia.

Biomarkers↗
PubMed2002

Fibroblast growth factor 8 isoform B overexpression in prostate epithelium: a new mouse model for prostatic intraepithelial neoplasia.

Fibroblast growth factor 8 isoform b (FGF8b), a mitogenic and transforming polypeptide, was demonstrated to be naturally up-regulated in prostatic premalignant and malignant lesions in men. We generated four independent lines of transgenic mice with targeted overexpression of FGF8b in the prostatic epithelium using an improved rat probasin promoter, ARR(2)PB. Transgene expression in the prostate tissue was readily demonstrated by reverse transcription-PCR and localized to the prostatic epithelium by in situ hybridization. The histopathology of the prostate tissues was followed in different age groups of the various lines but most extensively in one line (line 3), starting from 1 month of age up to 24 months. Prostatic hyperplasia appeared in the lateral and ventral prostates in some animals as early as 2-3 months and in other lobes between 6 and 16 months. Beginning at 5-7 months, dysplasia, akin to what may be considered low-grade prostatic intraepithelial neoplasia (LGPIN) in humans, was detected. During the first 14 months, 100% of animals exhibited multifocal epithelial hyperplasia; 35% also had areas of LGPIN. This profile changed in subsequent months (15-24 months) to a higher incidence of LGPIN (66%) along with high-grade PIN (HGPIN) lesions (51%). Similar to HGPIN, stromal proliferation and appearance of papillary hyperplasia with atypia displayed a delayed pattern. The affected stroma consisted primarily of the smooth muscle cell component. The incidence of chronic inflammation, mostly involving T cells, was higher in the prostate of the transgenic mice relative to controls; however, the presence of a direct correlation between inflammation and hyperplasia or preneoplastic lesions was not identified. These transgenic mice represent a "natural" animal model for investigating the mechanism of development and progression of prostatic diseases, such as prostatic hyperplasia and preneoplastic lesions.

Animals↗
PubMed1996

Bcl-2 immunoreactivity in prostate tumorigenesis in relation to prostatic intraepithelial neoplasia, grade, hormonal status, metastatic growth and survival.

The Bcl-2 protein prolongs cell survival by overriding apoptosis. To explore the role of Bcl-2 in prostate tumorigenesis, immunoreactivity for Bcl-2 was examined in untreated and androgen-deprived tumours and lymph node metastasis. Following the transurethral resection, 150 untreated patients were maintained under surveillance until death or for a minimum of 11 years, and castration was performed at symptomatic progression. The Bcl-2 index (BI) was defined as the percentage of immunoreactive cells in a tumour. The mean BI was 12 in the untreated tumours, and BI was significantly higher in high-grade tumours, mean BI 17, than in low-grade tumours, mean BI 6. There was no correlation between BI and stage or metastatic disease, nor did BI predict cancer-specific survival. In 16 androgen-deprived, but non-relapsed tumours, the mean BI was 54, at a mean time of 22 months after castration, indicating a permanent increase of Bcl-2 protein expression after androgen withdrawal. In six patients, tissues from the prostate tumour and obturator lymph node metastasis were available. Four primary tumours immunostained for Bcl-2, but only one metastasis stained. Foci of highgrade prostatic intraepithelial neoplasia (PIN) were present in 44 of the 150 untreated tumours. All PIN foci were intensely immunoreactive for Bcl-2, and mean BI was 79, suggesting that Bcl-2 protein expression is associated with early prostate tumorigenesis.

Aged↗
PubMed1998

Determination of gene and chromosome dosage in prostatic intraepithelial neoplasia and carcinoma.

OBJECTIVE: To review the utility of fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and comparative genomic hybridization (CGH) in the determination of gene and chromosome dosage in cancer specimens and to discuss the genetic association between prostatic intraepithelial neoplasia (PIN) and adenocarcinoma as detected by these three techniques. STUDY DESIGN: FISH, PCR, and CGH were applied to the same specimens to clarify discrepancies observed by a single technique alone and to further understand prostate carcinogenesis. RESULTS: The most common genetic alterations in PIN and carcinoma were (1) gain of chromosome 7, particularly 7q31; (2) loss of 8p and gain of 8q; and (3) loss of 10q, 16q and 18q. CONCLUSION: Using different techniques on the same specimen was useful to determine genetic relationships between cancer and its precursors. PIN and prostatic carcinoma foci have a similar proportion of genetic changes, but foci of carcinoma usually have more alterations. This supports the hypothesis that PIN is the most likely precursor of prostatic carcinoma.

Adenocarcinoma↗
PubMed2001

Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: Elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia.

This is a report of research efforts underway at the Arizona Cancer Center. These efforts build upon Larry Clark's unanticipated clinical prevention trial results: those results indicated that 200 microg/day of selenium in selenized yeast decreased prostate cancer risk by almost 60%. The trials underway address various phases of the possible preventive activity of selenium. The first of these, for men who are suspected to have prostate cancer but who have had a biopsy revealing no evidence of cancer, will test the ability of selenium to prevent the development of clinical prostate cancer. The second is for men with high-grade prostatic intraepithelial neoplasia; the trial will test whether selenium will prevent the development of prostatic cancer in this high-risk group. The third trial is for men who have been diagnosed with prostate cancer and are scheduled for prostatectomy: the trial is designed to test whether evidence of selenium-linked changes can be identified in the tissue removed at prostatectomy. The fourth trial is for men who have been diagnosed with prostate cancer but who have chosen neither surgery nor irradiation; this trial will evaluate whether treatment with selenium will inhibit the progress of prostate cancer. Together, these trials will provide important information as to the prostate cancer chemopreventive potential of selenium.

Anticarcinogenic Agents↗
PubMed1996

Expression of nm23-H1 in prostatic intraepithelial neoplasia and adenocarcinoma.

The product of the nm23-H1 gene has been reported to be related to the metastatic potential of several tumors. Although several studies have characterized the expression of the nm23-H1 gene product in prostatic adenocarcinoma, little is known of the expression of this protein in prostatic intraepithelial neoplasia (PIN), a putative precancerous lesion. The authors used immunohistochemistry to examine the expression of the nm23-H1 protein in PIN as well as benign and malignant prostatic tissue. A monoclonal antibody to nm23-H1 (Novocastra, Newcastle upon Tyne, UK, clone 37.6) and a biotin/strepavidin detection system were used for antigen localization. Weak to moderate immunostaining was consistently detected in the benign glandular epithelium of 28 radical prostatectomy specimens. In contrast, strong immunostaining was detected in the glandular epithelium in PIN lesions of 19 radical prostatectomy specimens examined. Strong immunostaining was also frequently detected in the malignant cells of 39 localized prostatic adenocarcinomas, as well as 7 metastatic lesions. These findings show a phenotypic similarity of PIN to prostatic adenocarcinoma with respect to nm23-H1 expression. Furthermore, strong expression of nm23-H1 likely represents an early event in the development of prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed2002

Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia.

The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.

Animals↗
PubMed2003

Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice.

Accurate determination of the contributions of oncogenes toward tumor progression requires their regulation. Herein, we created transgenic mice with prostate-specific expression of ligand-inducible FGFR1 or FGFR2, based on lipid-permeable dimerizing molecules, called chemical inducers of dimerization. Despite extensive homology and equivalent expression by both chimeric receptors in the ventral prostate gland, only FGFR1 triggers detectable nuclear translocation of Erk and progression to prostatic intraepithelial neoplasia (PIN). Induction of PIN grade I-II, indicated by multiple layers of atypical cells, is seen consistently by 12 weeks of chemical inducers of dimerization treatment. By 6 months, more extensive nuclear atypia, thickened "reactive" stroma, and basement membrane herniation occurs, corresponding to PIN IV. By timed removal of FGFR1 signaling, we show that induced hyperplasia is reversible until extensive intraductal vascularization occurs, but continued progression requires prolonged FGFR1 signaling. Additionally, by highlighting differences between the two receptors and creating the foundation for controlling FGFR1 signaling during prostate cancer progression, a model of early stage prostate cancer is established for developing targeted intervention directed toward the FGFR signaling axis.

Animals↗
PubMed1991

Morphonuclear relationship between prostatic intraepithelial neoplasia and cancers as assessed by digital cell image analysis.

Using digital cell image analysis performed on Feulgen-stained nuclei, the nuclear characteristics of prostatic neoplasia, ranging from benign (benign prostatic hyperplasia [BPH]), through dysplastic (prostatic intraepithelial neoplasia [PIN] 1-3), to carcinoma were studied. Four histopathologic groups were studied: group IA (18 samples) contained BPH, PIN 1, and PIN 2 lesions that were from 9 prostate samples free of cancer. Group IB (23 samples) was identical to group IA, contained also BPH, PIN 1, and PIN 2 lesions, but lesions that were from 7 prostate samples where malignant foci were detected elsewhere. Group II (11 samples) were PIN 3 specimens. Group III (24 samples) were carcinomas. Features of neoplastic nuclei were quantified objectively through morphometric (nuclear size), densitometric (nuclear DNA content), and textural (chromatin organization and heterogeneity) parameters. Cell kinetic parameter, i.e., cell proliferation index, was assessed from the densitometric measurement. The proliferation index was significantly higher in PIN 3 and cancers as compared to BPH, PIN 1, and PIN 2 tissues. Morphonuclear characteristics were also dramatically distinct among the four groups. Indeed, the nuclear size and the hyperchromatism of severe prostatic dysplasia were similar to those of carcinomas, these two lesion types showing mean parameter values that were higher as compared to BPH, PIN 1, and PIN 2 lesions. Finally, benign tissues related to mild or moderate dysplasia taken in histologic material in which cancer was present already share the morphonuclear characteristics of severe dysplasia, although they are nonproliferating.

Cell Nucleus↗
PubMed1994

Prostatic intraepithelial neoplasia. Development of a Bayesian belief network for diagnosis and grading.

The diagnosis and grading of prostatic intraepithelial neoplasia (PIN) are affected by uncertainties that arise from the fact that almost all our knowledge of PIN histopathology is not expressed in numeric form but rather in descriptive linguistic terms, words and concepts. A Bayesian belief network (BBN) was used to reduce the problem of uncertainty in diagnostic clue assessment while considering the dependencies between elements in the reasoning sequence. A shallow network was developed with an open-tree topology, with a root node containing the diagnostic alternatives and seven first-level descendant nodes for the diagnostic clues. One of these nodes was based on tissue architecture and the others on cell features. The results obtained with prototypes of relative likelihood ratios showed that beliefs for the diagnostic alternatives are very high. The network can grade and differentiate PIN lesions from other prostate lesions with certainty. A number of diagnostic clues greater than seven did not significantly improve network performance, whereas a reduced number of clues resulted in decreased beliefs. A BBN for PIN diagnosis and grading offers a descriptive classifier that is readily implemented and allows the use of linguistic, fuzzy variables. A BBN allows the accumulation of evidence presented by diagnostic clues, each offering only weak evidence.

Bayes Theorem↗
PubMedDate not supplied

Immunohistochemical evaluation of type IV collagenase (72-kd metalloproteinase) in prostatic intraepithelial neoplasia.

The aim of this study was to investigate the expression of type IV collagenase (72-kd metalloproteinase, MMP-2) in prostatic intraepithelial neoplasia (PIN) in relation to normal prostate (NP) and prostatic adenocarcinoma (PAc). Twenty formalin-fixed, paraffin-embedded prostatectomy specimens, in which NP, PIN and PAc were present, were immunohistochemically examined. The NP ducts and acini not contiguous with PIN and PAc showed slight MMP-2 immunostaining in the secretory cells, with some increase in intensity at the apical border, and moderate to strong immunoreactivity of some basal cells. In NP adjacent to PIN and PAc, rare ducts and acini showed strongly stained cells either isolated or in small groups of two, located within the thickness of the epithelium, close to the basement membrane. In the majority of PIN ducts and acini, the stratified secretory cells showed moderate staining. Most of these ducts and acini also showed strongly stained cells, which were mostly isolated, and either in contact with the basement membrane or scattered among the secretory cells. Low and high grade PIN showed some difference in the frequency of dark cells, which were more numerous in the latter. A small group of neoplastic acini adjacent to high grade PIN (early invasive adenocarcinoma) was observed in one of the 20 cases. Intense immunostaining was present in the acini originating from the PIN lesion. MMP-2 immunostaining of PAc was heterogeneous in intensity and location. Cribriform and solid/trabecular PAc showed weak cytoplasmic immunostaining; both moderately and intensely stained cells were seen in the cell layer adjacent to the stroma, intense immunostaining was shown by small clusters of neoplastic cells or single neoplastic cells located in the stroma. In acinar PAc, weak cytoplasmic immunostaining for MMP-2 was seen throughout most areas of the tumours, whereas moderately and intensely stained cells were observed less frequently than in cribriform and solid/trabecular adenocarcinoma. Intense immunostaining of single or small clusters of neoplastic cells located in the stroma was occasionally observed and, as with cribriform and solid/trabecular PAc, mainly located towards the periphery of the tumour nodules. Occasional ducts and acini with PIN and foci of PAc were either completely negative or very weakly stained. In conclusion, MMP-2 immunostaining increases progressively from NP, through PIN, up to invasive PAc. These results directly support the hypothesis that increased expression of metalloproteinases is a marker of malignant conversion.

Adenocarcinoma↗
PubMed2000

Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer.

BACKGROUND: Oxidative stress results in damage to cellular structures and has been linked to many diseases, including cancer. The authors sought to determine whether the expression of three major antioxidant enzymes, copper-zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), and catalase, was altered in human prostate carcinoma and its likely precursor, high grade prostatic intraepithelial neoplasia (PIN). The level of reactive oxygen species damage was evaluated by measuring the expression of the DNA adduct 8-hydroxydeoxyguanosine. METHODS: The authors evaluated the tissue expression of the antioxidant enzymes in prostate carcinoma by immunohistochemistry, immunogold electron microscopy, and enzymatic assay. The polymerase chain reaction was used to amplify and screen tissue specimens for the genes of SOD1, SOD2, and extracellular SOD (SOD3). Matched paraffin embedded tissue sections were evaluated by RNA in situ hybridization for expression of SOD1 and immunohistochemically for the DNA adduct 8-hydroxydeoxyguanosine. RESULTS: All prostatic tissues, including cancer, displayed immunoreactivity for the three antioxidant enzymes in epithelial cells, with no staining of the stroma, inflammatory cells, or endothelial cells. The number of immunoreactive cells was greater in benign epithelium than in PIN and cancer for each enzyme. The mean percentage and intensity of immunoreactive cells was greatest for SOD2, intermediate for SOD1, and lower for catalase. Staining in cancer was heterogeneous. Immunogold ultrasound studies revealed strong mitochondrial labeling for SOD2, which was greater in benign epithelium than in cancer; SOD1 labeling was invariably weaker, with nuclear labeling in benign epithelium and cytoplasmic labeling in cancer cells. There was no difference in enzyme activity for the three antioxidant enzymes between benign epithelium and cancer. No mutations were found in the 5 exons of SOD1, 5 exons of SOD2, and 3 exons of SOD3, except for 3 of 20 cases with polymorphisms for exon 3 of SOD1. Intense nuclear immunoreactivity for 8-hydroxydeoxyguanosine was present in fewer than 3% of epithelial cells, with no apparent differences among benign epithelium, PIN, and cancer. CONCLUSIONS: SOD1, SOD2, and catalase had lower expression in PIN and prostate carcinoma than in benign epithelium. The number of immunoreactive cells in PIN was similar to cancer, indicating that these are closely related. Enzyme activities were variable, with no difference between benign epithelial cells and cancer, although this lack of change in enzyme activity could have been due to the presence of contaminating benign cells within the cancer specimens. The results of reactive oxygen species damage were found only in the epithelium and not in the stroma. Expression of the DNA adduct 8-hydroxydeoxyguanosine was present in fewer than 3% of cells, with no apparent differences among benign epithelium, PIN, and cancer. These findings suggest that oxidative stress is an early event in carcinogenesis.

Aged↗
PubMed1993

Significance of high-grade prostatic intraepithelial neoplasia on needle biopsy.

We studied 33 cases with an initial needle biopsy of the prostate that showed only high-grade prostatic intraepithelial neoplasia (PIN 2-3), for which follow-up biopsies were available. Twenty-four men (73%) were shown to have adenocarcinoma either on a simultaneous (14 patients) or subsequent (10 patients) biopsy. The grade of PIN (grade 2 v 3), rectal examination findings, and transrectal ultrasound results proved not to be significantly different in patients with proven adenocarcinoma compared with those without proven carcinoma. In contrast, serum prostate-specific antigen (PSA) concentrations were elevated in 90% of patients with carcinoma compared with only 50% of those with a benign follow-up biopsy. Persistent elevation of serum PSA concentration was seen in only one of three patients with serial PSA measurements and a benign follow-up biopsy. Notably, all patients with carcinoma for whom we had serial measurements of serum PSA levels had persistent elevation. The finding of high-grade PIN on needle biopsy often represents a sampling problem with carcinoma nearby. Consequently, the finding of high-grade PIN on needle biopsy merits vigorous follow-up, including rebiopsy. In particular, patients with increased serum PSA appear to be at greater risk of harboring prostatic adenocarcinoma. However, a significant number of patients with high-grade PIN on initial biopsy may not have evidence of carcinoma on repeat biopsy. Thus, radical prostatectomy or radiotherapy for PIN is not warranted.

Adenocarcinoma↗