Extent Of Prostatic Intraepithelial Neoplasia Research Articles

Precursors of prostate cancer

High-grade prostatic intraepithelial neoplasia (PIN) is the only accepted precursor of prostatic adenocarcinoma, according to numerous studies of animal models and man; other proposed precursors include atrophy and malignancy-associated changes (with no morphologic changes). PIN is characterized by progressive abnormalities of phenotype and genotype that are intermediate between benign prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. The only method of detection of PIN is biopsy because it does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultrasonography. The mean incidence of PIN in biopsies is 9% (range, 4%-16%), representing about 115,000 new cases of isolated PIN diagnosed each year in the United States. The clinical importance of PIN is its high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent carcinoma, especially when multifocal or observed in association with atypical small acinar proliferation (ASAP). Carcinoma develops in most patients with PIN within 10 years. Androgen deprivation therapy and radiation therapy decrease the prevalence and extent of PIN, suggesting that these forms of treatment may play a role in prevention of subsequent cancer. Multiple clinical trials to date of men with PIN have had modest success in delaying or preventing subsequent cancer.

Irs2 Inactivation Suppresses Tumor Progression in Pten+/− Mice

Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-alpha (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten(+/-) mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten(+/-) mice were crossed with Irs2(+/-) mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten(+/-) mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten(+/-) mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten(+/-) mice by stimulating both Myc and DNA synthesis.

Morphological changes induced by androgen blockade in normal prostate and prostatic carcinoma

Maximal androgen blockade (MAB), combining a luteinizing hormone releasing hormone (LHRH) agonist and a pure or non-steroidal anti-androgen, induces significant morphologic changes in the prostate. The tumor volume, density, capsular penetration, and surgical margin involvement are strongly reduced following such treatment. On histology, normal prostate tissue and tumor undergo marked atrophy and shrinkage. Although residual cancer cells are readily identifiable in most cases, they may often be sparse and easily overlooked. The increased Gleason score apparent after MAB is most likely related to fragmentation of acinar structures, and grading is not recommended following MAB. Residual cancer cells show features of lower activity and increased apoptosis. Such therapy-induced changes may be reversible, although occasional clones of cancer cells are apparently not affected and have probably developed resistance. Finally, MAB leads to marked but reversible morphologic changes and reduction in prevalence and extent of prostatic intra-epithelial neoplasia (PIN). Monotherapy using a variety of agents causes comparable but often less extensive changes.

High-grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound. Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

High-grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound. Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

Precancerous Lesions and Conditions of the Prostate

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate-specific antigen. PIN is characterized by progressive abnormalities of phenotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma, according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via suppression of vascular endothelial growth factor production. Prostatic carcinoma is also likely to arise from precursor lesions other than high-grade PIN such as low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy.

Prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely pre-invasive stage of adenocarcinoma, a decade after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen concentration or its derivatives and cannot be detected by ultrasound. Most studies suggest that most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype that are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

Prevalence and distribution of prostatic intraepithelial neoplasia in salvage radical prostatectomy specimens after radiation therapy.

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer. The effect of radiation therapy (RT) on the prevalence of PIN is uncertain. We studied 86 patients who underwent salvage radical prostatectomy after irradiation failure at the Mayo Clinic. The prevalence, volume, multicentricity, spatial proximity to cancer, and architectural patterns of PIN were evaluated. High-grade PIN was identified in 53 (62%) of 86 prostatectomy specimens. Multiple architectural patterns were usually observed, including tufting in 87%, micropapillary in 66%, cribriform in 38%, and flat in 17%. The mean volume of PIN was 0.12 cm3 (range, 0.05-1.20 cm3). PIN was usually multicentric (70%), with a mean number of PIN foci of 2.5 (range, 1-10). Ninety-four percent of PIN foci were located within 2 mm of invasive cancer. There was no correlation between PIN and pathologic stage, surgical margin, tumor size, DNA ploidy, post-RT Gleason score, time interval from RT to biopsy-proven recurrence, postoperative prostate-specific antigen level, distant metastasis-free survival, or cancer-specific survival. Our examination of salvage radical prostatectomy specimens indicated that the prevalence and extent of PIN appeared to be reduced after RT compared to published studies of prostatectomies without prior RT.

Prostatic intraepithelial neoplasia (PIN) and other prostatic lesions as risk factors and surrogate endpoints for cancer chemoprevention trials

The most efficient strategy for chemoprevention clinical trials are short-term studies which focus on surrogate endpoint biomarkers (SEBs) in high-risk target populations. High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer, and is found in a significant number of routine contemporary needle biopsies without cancer. The frequency and extent of PIN are decreased with androgen deprivation therapy, suggesting that it is a suitable endpoint biomarker for modulation. Potential SEBs for screening chemopreventive agents for prostate cancer in short-term Phase II trials include (1) histologic premalignant lesions, such as high-grade PIN; (2) biochemical markers, including prostate-specific antigen (PSA) serum concentration; and (3) morphometric markers, including nuclear texture, shape, and roundness; size and number of nucleoli; and number of apoptotic bodies; (4) proliferation markers, including MIB-1 and PCNA; (5) genetic markers, including nuclear DNA content (ploidy), oncogene c-erbB-2 (HER-2/neu) expression, fluorescence in situ hybridization for chromosome 8; and PSA-producing cells in the blood detected by reverse transcriptase polymerase chain reaction; and (6) differentiation markers, such as microvessel density as a determinant of angiogenesis. Each of these endpoint biomarkers is measured easily and accurately in serum or in tissue specimens such as formalin-fixed, paraffin-embedded needle biopsies, and may be modifiable by intervention. The clinical utility of these biomarkers as modulatable endpoints in prostate cancer chemoprevention needs to be demonstrated in future clinical trials.

Progression of prostatic intraepithelial neoplasia to early invasive adenocarcinoma.

High-grade prostatic intraepithelial neoplasia is the most likely precursor of adenocarcinoma. This report describes the diagnostic criteria for prostatic intraepithelial neoplasia, its clinical significance, and the evidence suggesting that it progresses to prostatic adenocarcinoma. We reviewed the published evidence linking prostatic intraepithelial neoplasia and prostate cancer. Prostatic intraepithelial neoplasia has a high predictive value as a marker for adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. Most studies suggest that, if untreated, prostatic intraepithelial neoplasia will progress to early carcinoma, although only indirect evidence exists to support this hypothesis. Androgen deprivation therapy decreases the prevalence and extent of prostatic intraepithelial neoplasia, suggesting that this form of treatment may play a role in chemoprevention. Prostatic intraepithelial neoplasia does not appear to elevate serum PSA concentration. It is associated with progressive abnormalities of phenotype and genotype which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. Virtually all data indicate that high-grade prostatic intraepithelial is premalignant, accounting for most if not all cases of prostate cancer.

Morphometric Analysis and Clinical Followup of Isolated Prostatic Intraepithelial Neoplasia in Needle Biopsy of the Prostate

Purpose We evaluate the significance of grade and extent of isolated prostatic intraepithelial neoplasia in prostate needle biopsies as a predictor of cancer on repeat biopsy. Materials and Methods We reviewed our experience with 58 men 50 years or older who had isolated prostatic intraepithelial neoplasia on initial prostate needle biopsy during a prostate specific antigen (PSA) based screening trial for prostate cancer. All 58 men underwent repeat biopsy to follow the initial findings of prostatic intraepithelial neoplasia. We assessed the relationship of patient age, digital rectal examination, serum PSA concentration, PSA density, prostatic intraepithelial neoplasia grade, number of foci of neoplasia and linear extent of prostatic intraepithelial neoplasia in the initial biopsy specimen to the finding of cancer on the repeat biopsy. We also compared the cancer detection rate in the 58 ment with and 427 without prostatic intraepithelial neoplasia in the same screening trial. Results Of 21 men with low grade and 37 with high grade prostatic intraepithelial neoplasia 4 (19 percent) and 19 (51 percent), respectively, had cancer on repeat biopsy (p less than 0.02), compared to 82 of 427 (19 percent) without cancer or prostatic intraepithelial neoplasia on the initial biopsy. High grade prostatic intraepithelial neoplasia was a significant predictor of malignancy on repeat biopsy (p greater than 0.05). The number of foci of neoplasia and the linear extent of prostatic intraepithelial neoplasia on initial biopsy were not predictive of cancer on repeat biopsy. Conclusions Our results demonstrate that the presence of high grade prostatic intraepithelial neoplasia is a strong predictor of prostate cancer in men with elevated serum PSA concentrations and they should be followed with repeat biopsy.