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PubMed2001

High grade prostatic intraepithelial neoplasia is a disease.

High grade prostatic intraepithelial neoplasia (PIN) is now widely accepted as the main premalignant lesion that has the potential to progress to prostate adenocarcinoma. High grade PIN is a standard diagnosis that must be included as part of the reported pathologic evaluation of prostate biopsies. Premalignant lesions that affect other organs have been identified and are treated when diagnosed such that the premalignant lesions itself are a disease (eg, carcinoma in situ of the bladder, colon polyps, and cervical dysplasia). Urologists should recognize that high grade PIN is a dangerous lesion and that it should be aggressively managed either by saturation biopsies of the prostate following the diagnosis of high grade PIN, or the more common recommendation--repeated prostate biopsies every 3 to 6 months for 2 years, then annually. Treatment of these precancerous lesions would appear to be of clinical benefit notwithstanding the potential for cancer prevention. These clinical benefits would reduce morbidity, enhance the quality of life, delay surgery or radiation, and increase the interval for surveillance requiring invasive procedures.

Adenocarcinoma↗
PubMed1993

Computerized static DNA ploidy analysis of prostatic intraepithelial neoplasia.

The microscopic features of prostatic intraepithelial neoplasia (PIN) are said to identify a precursor of prostatic adenocarcinoma (PC). We investigated this sequence of neoplastic progression by studying the relationship of PIN and PC by static ploidy analysis so that PIN and PC nuclei could be distinguished morphologically from each other and separately analyzed. From 51 archival cases of PC with coexistent high-grade PIN (PIN grades II and III) 50 control nuclei, 100 PIN nuclei, and 100 carcinoma nuclei per case were identified and digitized in corresponding Feulgen-stained slides. Control and PIN ploidy histograms fit a log-normal distribution, whereas malignant nuclei fit a rectangular distribution. When the histogram patterns were classified, the incidence of aneuploidy was 25% in PIN and 41% in PC. By case, the concordance of ploidy between PIN and PC was heterogeneous, yet the DNA ploidy of PIN and the corresponding PC was significantly associated. In four cases, PIN was DNA aneuploid while the associated PC was DNA diploid. These results support the hypothesis that high-grade PIN is a neoplastic precursor of prostatic adenocarcinoma and suggest that further karyotypic instability may result in invasive adenocarcinoma with different DNA content detectable by image analysis.

DNA, Neoplasm↗
PubMed1996

Interobserver variability in the diagnosis of high-grade prostatic intraepithelial neoplasia and adenocarcinoma.

High-grade prostatic intraepithelial neoplasia (PIN) is a strong predictor of carcinoma when identified in small-needle biopsy specimens. However, the diagnostic variability of PIN is unknown. Eight pathologists reviewed 321 prostatic biopsy specimens to assess the variability of the diagnosis of high-grade PIN and carcinoma. All of the specimens were classified as negative, high-grade PIN, suspicious for high-grade PIN, carcinoma, or suspicious for carcinoma, more than one diagnosis was permitted, except for negative. We compared diagnoses made by two observers by pairing them for negative versus high-grade PIN, negative versus carcinoma, high-grade PIN versus carcinoma, and all diagnostic categories together. Mean kappa coefficient values for 28 interobserver combinations were 0.451, 0.845, 0.669, and 0.482, respectively, for each of the four comparison combinations considered. Our results indicate a high level of agreement, "almost perfect" (kappa = 0.81-1.0) for carcinoma, "moderate" (kappa = 0.41-0.60) for high-grade PIN, and "substantial" (kappa = 0.61-0.81) for high-grade PIN versus carcinoma. We found that variability was related to the level of interest in prostatic pathology, the conditions of the study, the subjective application of diagnostic criteria, and the influence of peers and clinical colleagues.

Adenocarcinoma↗
PubMed1995

Epidemiology of high grade prostatic intraepithelial neoplasia.

The prevalence of high grade prostatic intraepithelial neoplasia (HGPIN), the age at which this lesion starts and the potential racial or ethnic differences in its distribution are poorly documented. HGPIN is becoming increasingly implicated as a premalignant lesion for clinically significant prostatic carcinoma (PCa) with mounting evidence linking it to carcinoma according to morphologic immunohistochemical and recent genomic studies. We describe our experience with the age and race distribution of HGPIN resulting from two study populations of African-American (AA) and Caucasian (C) males. The first component of this report describes an autopsy study aimed at determining the prevalence of latent PCa and HGPIN in AA and C men 20 years of age or older; 370 (218 AA and 152 C) consecutive step-sectioned, totally embedded prostate glands were microscopically evaluated and mapped for HGPIN and PCa. HGPIN was first identified in the third decade and increased steadily with age. Latent PCa increased steadily with age with no significant difference in the prevalence between AA and C males in any age group (3rd to 8th decades). HGPIN, on the other hand, was more prevalent in AA men with 18, 31, 69, 78 and 86% in their 4th, 5th, 6th, 7th and 8th decades harboring the lesion. The corresponding figures for C men were 14, 21, 38, 50 and 63% respectively. When HGPIN was quantitated as focal and extensive according to the degree of glandular involvement, extensive HGPIN appeared earlier in AA males under 60 years of age compared to C males cohort. The difference in age distribution appeared to follow a chronological pattern, with HGPIN in AA preceding that of C males by approximately a decade. The second component of this report describes a surgical series of 345 consecutive radical prostatectomies from patients (155 AA and 190 C) with clinically localized PCa, which were thoroughly evaluated microscopically by two urologic pathologists. Similar to the findings in the autopsy study, extensive HGPIN was more prevalent in AA men 60 years of age or younger (57% vs. 33%). In both races, the mean percentage of the gland involved by HGPIN decreased with advancing age in contrast to the mean tumor volume that increased with patient age. These findings indicating a different prevalence of HGPIN in the two racial groups may help explain the higher incidence of prostatic cancer in African-Americans.

Adenocarcinoma↗
PubMed2006

Allelotyping analysis at chromosome 13q of high-grade prostatic intraepithelial neoplasia and clinically insignificant and significant prostate cancers.

BACKGROUND: Loss of heterozygosity (LOH) at 13q is one of the most common chromosomal alterations in high-stage prostate cancer, yet little is known about genetic changes in earlier-stage prostate cancer. METHODS: We used five microsatellite markers at 13q14, 21, and 33 to compare LOH frequencies in 51 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 21 cases of incidental prostate cancers (IPCs), 31 cases of latent prostate cancers (LPCs), and 102 cases of clinical prostate cancers (CPCs). RESULTS: The frequency of LOH at 13q with at least 1 marker was 0%, 38%, 56%, and 49% in HGPIN, IPCs, LPCs, and CPCs, respectively. No statistically significant difference was found between the types of prostate cancer. Allelic loss at 13q14 was significantly more frequent in pT4 tumors than in earlier-stage tumors (P=0.011). CONCLUSIONS: Allelic loss at 13q is not only an important event in the metastasis of prostate cancer, but also associated with the initiation of the tumor.

Alleles↗
PubMed2001

[Prevalence of prostatic intraepithelial neoplasia in Spain].

OBJECTIVE: To study the prevalence of high grade prostatic intraepithelial neoplasia in a Spanish population and to compare it with the prevalence in Caucasians of other countries and Afro-Americans. METHODS: 162 prostates obtained at autopsy from Spanish men aged 20-80 years, were fixed in 10% formalin and slices perpendicular to the posterior margin were made every 3-4 mm along its entire length. All blocks were embedded in paraffin and examined microscopically. Mapping of focality and site of the high grade prostatic intraepithelial neoplasia was done for each case. The Wayne University autopsy study was used for comparison of the prevalence in other countries and races. RESULTS: 146 prostates from men with a mean age of 48.5 years were considered valid for histological analysis. There were 42 high grade prostatic intraepithelial neoplasia; 20 were focal and 22 multifocal. By age group, the prevalence of high grade prostatic intraepithelial neoplasia were 7.1%, 14.7%, 28.5%, 33.3%, 45.4% and 51.8% for the 3rd, 4th, 5th, 6th, 7th, and 8th decades. CONCLUSIONS: High grade prostatic intraepithelial neoplasia begins to manifest in the Spanish population after the 3rd decade. It is usually focal and peripheral, and significantly increases with age and becomes multifocal. Its prevalence in the Spanish population is moderately lower than in American Caucasians and significantly lower than in Afro-Americans.

Adult↗
PubMed2004

Prostatic intraepithelial neoplasia: an update.

High-grade prostatic intraepithelial neoplasia (HGPIN) is commonly encountered on prostate needle biopsies and, based on epidemiologic, molecular, and animal models, has proven to be the most significant risk factor for prostate cancer and likely represents the premalignant phase of prostatic adenocarcinoma. This lesion is characterized by cellular proliferations within pre-existing ducts and glands, with nuclear and nucleolar enlargement similar to prostate cancer. However, unlike cancer, HGPIN retains a basal cell layer identifiable by immunohistochemistry with the basal cell-specific antibody cytokeratin 34bE12. The incidence of HGPIN identified in needle biopsies is as high as 25%, increases with age, and coexists with prostate cancer in approximately 85% of cases. There appears to be no causal relationship between HGPIN and serum prostate-specific antigen (total, percent free, or density) or radiographic characteristics on transrectal ultrasound. In a large series, the identification of HGPIN on initial needle biopsy is associated with about a 35% risk of prostate cancer on subsequent biopsies. Thus, the finding of HGPIN on prostate needle biopsy necessitates a second biopsy in a patient eligible for curative treatment. As a precursor lesion, HGPIN is currently a target for chemopreventive strategies, including antiandrogens and nutritional supplementation.

Biopsy↗
PubMed1994

Comparison of DNA ploidy in prostatic intraepithelial neoplasia and invasive carcinoma of the prostate: an image cytometric study.

Prostatic intraepithelial neoplasia (PIN) is regarded as the most important premalignant lesion of prostatic epithelium. The aim of this investigation was to find clues to formal pathogenesis of prostatic cancer. For this purpose DNA ploidy (determined by means of image cytometry [ICM] using 4-microns-thick Feulgen-stained paraffin sections) of PIN and invasive carcinoma was compared. Prostatic tissue of 72 patients (mean age, 67.5 years; 82 areas with carcinoma and 71 areas with PIN) was examined. In 44 cases PIN and carcinoma were coexistent in the same prostates, the PIN grade being high in 77% of these cases (P < .05). In higher-grade PIN and higher-grade carcinoma the c-values, 2.5c-exceeding-rate, and aneuploidy rate increased (P < .01). Carcinomas associated with diploid PIN (either low or high grade) showed diploidy and aneuploidy in an equal number of cases, whereas 70% of aneuploid PIN cases (all high grade) were associated with aneuploid invasive carcinomas (P < .01). Conversely, in 71% of the cases with aneuploid carcinoma the coexistent PIN (either low or high grade) was diploid. Our findings show that aneuploidy can be acquired at a preinvasive stage of carcinogenesis in the prostate and suggest that aneuploid high-grade PIN might be regarded as a precursor of some but not all aneuploid prostatic carcinomas. Image cytometry analysis seems to be a promising method for further subclassification of high-grade PIN lesions into groups with putatively lower or higher risk. However, further investigation is necessary to confirm the clinical importance of these results.

Adult↗
PubMed2001

High-grade prostatic intraepithelial neoplasia as an exposure biomarker for prostate cancer chemoprevention research.

There is a tremendous need for exposure biomarkers, which need to function as intermediate end-points in cancer chemoprevention studies. Likely candidates include process biomarkers, atypical adenomatous hyperplasia, and a newly identified atrophic state. High-grade prostatic intraepithelial neoplasia (HGPIN) has the potential to be a useful exposure biomarker, having substantial predictive value for prostate cancer in chemoprevention trials. A limitation of the use of HGPIN as a biomarker is accessibility, since it requires the use of a highly invasive procedure that would not normally be applied unless malignancy is suspected to be present. However, most other biomarkers of prostatic tissue are similarly invasive. The HGPIN lesion appears to be highly measurable; however, problems of sampling coupled with the heterogeneity of the prostate raise questions about the degree to which the presence of HGPIN can be seen to characterize a given person's prostate gland. HGPIN has the advantage that it appears to be quite highly proximal to the development of cancer and to be modifiable. It remains less clear to what degree it reflects the exposures that are believed to alter prostate cancer risk. HGPIN has been identified as a clinical entity only recently and much additional research on the utility of this marker is needed.

Anticarcinogenic Agents↗
PubMed1999

Androgen receptor expression in prostatic intraepithelial neoplasia and cancer.

PURPOSE: Androgen receptors are present in virtually all epithelial cells of the prostate, including benign epithelium, high grade prostatic intraepithelial neoplasia and cancer. However, there have been variable results regarding the clinical significance of cells expressing androgen receptors in prostate cancer. We evaluated the predictive accuracy of androgen receptor expression in prostatic intraepithelial neoplasia and cancer for clinical progression and survival in patients with organ confined prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: The study consisted of 172 previously untreated patients who underwent radical prostatectomy at our clinic between 1987 and 1991 with intermediate to high grade (Gleason score 6 to 9), pathological stage T2 cancer and negative surgical margins. Mean followup was 7.4 years (range 1.2 to 10.1). Mouse monoclonal anti-human androgen receptor antibody was used for immunohistochemical studies on select tissue sections from each case. We counted 100 nuclei from 3 separate areas of benign epithelium, prostatic intraepithelial neoplasia and cancer (total 300 nuclei for each diagnostic category) for each case. Mean nuclear androgen receptor expression was determined from the mean of the individual cases for each diagnostic category. Intensity was also evaluated using a subjective scale from 0 (no staining) to 3 (strong staining). We determined the correlation of clinical progression and the number of androgen receptor immunoreactive prostatic intraepithelial neoplasia or cancer nuclei, and then performed multivariate analysis which included deoxyribonucleic acid ploidy, radical prostatectomy Gleason score and preoperative serum prostate specific antigen using the Cox proportional hazards model. Progression was defined as a positive biopsy, positive bone scan or biochemical progression (postoperative serum prostate specific antigen greater than 0.2 ng./ml.). RESULTS: Nuclear immunoreactivity for androgen receptors was observed in all cases. Mean percent of immunoreactive nuclei was higher in benign epithelium than in prostatic intraepithelial neoplasia and cancer (56.3, 46.1 and 53.6%, respectively, pairwise comparisons p <0.05 for each pair). With rare exceptions, basal cells in benign epithelium and prostatic intraepithelial neoplasia were negative. The most intense nuclear staining was observed in benign epithelium. Immunoreactivity was also faint but detectable in the cytoplasm in prostatic intraepithelial neoplasia but not in benign epithelium or cancer. Mean number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer was not a significant univariate or multivariate predictor of clinical and/or biochemical progression, or all cause survival (all p >0.05). CONCLUSIONS: Androgen receptor expression was present in all cases of benign epithelium, prostatic intraepithelial neoplasia and cancer. The greatest extent and intensity of expression were observed in benign epithelium, with about half of the nuclei showing intense immunoreactivity. The number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer in patients with organ confined prostate cancer treated with radical prostatectomy was not predictive of progression or survival.

Adenocarcinoma↗
PubMed2002

Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor alpha allele in the prostate epithelium.

Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor alpha (RXRalpha) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXRalpha function. There was also a significant change in the profile of secretory proteins in the RXRalpha mutant prostate relative to littermate controls with intact RXRalpha allele. Histopathologically, homozygous RXRalpha-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at approximately 10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10-15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXRalpha, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.

Alleles↗
PubMed1998

High grade prostatic intraepithelial neoplasia in military working dogs with and without prostate cancer.

BACKGROUND: High grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of human prostate cancer and is commonly found in men undergoing prostatic needle biopsy for suspected cancer. Recent work has demonstrated that pet dogs, like humans, develop PIN spontaneously and in association with prostate cancer. Pet dogs are the most domesticated animal, sharing the habitat and oftentimes the diet of their owners. If PIN and prostate cancer are strongly related to environmental factors, then the prevalence of these findings might differ in a population of dogs such as military working dogs which is not exposed to the habitat and diet of humans. In this study, we determined the prevalence of PIN in prostates of aged military working dogs with and without prostatic adenocarcinoma. METHODS: Cases were selected from the military working dog slide and tissue archive at the Armed Forces Institute of Pathology, Washington, DC. The most recent 329 necropsies (1991 to 1996) were examined histologically by multiple reviewers; of these, 199 dogs (60%) were found to have evaluable prostatic tissue. In addition, the most recent 50 necropsies (1958 to 1996) with the diagnosis of prostatic cancer were examined, of which 25 cases (50%) were found to have evaluable prostatic adenocarcinoma. In most cases, a single large transverse section of prostatic tissue was available for review. Medical records for each dog were reviewed independently, and age, clinical history, indications for euthanasia, and other health problems were recorded. RESULTS: High grade PIN was identified in 3% of dogs (6 of 199 dogs) without prostate cancer. A total of 50.8% of dogs in this study group (101 of 199 dogs) were known to be sexually intact, 26.7% of dogs (53 of 199 dogs) were castrated, and the status of the remaining 22.6% of dogs (45 of 199 dogs) was unknown. High grade PIN was present in 18 of 25 dogs (72%) with prostatic adenocarcinoma. Of these cases, 11 dogs (44%) were castrated, 4 dogs (16%) were intact, and the status of 10 dogs (40%) dogs was unknown. Gleason scores ranged from 6 to 10, with a mean of 8.4 and a median of 8. CONCLUSIONS: High grade PIN is present in a small but substantial number (3%) of military working dogs. Of military working dogs with prostatic adenocarcinoma, 72% had high grade PIN. The true prevalence in each of these cohorts is likely to be higher given the sampling variation inherent in evaluating a single random histologic section. Aged male dogs seem to have substantial clinical utility as an animal model for prostatic carcinogenesis. We recommend that serial sectioning and total embedding of the prostate should be used to more thoroughly characterize premalignant and malignant diseases in aged military working dogs. This method will provide important data to determine whether a model of spontaneous PIN in elderly dogs may have clinical utility in developing strategies directed toward preventing and treating prostate.

Adenocarcinoma↗
PubMed2006

High grade prostatic intraepithelial neoplasia with squamous differentiation.

An unusual variant of prostatic intraepithelial neoplasia with prominent and extensive squamous differentiation is described. The lesion was identified in the transition zone of a 79 year old man with a three year history of increasing urinary obstructive symptoms and a clinical diagnosis of benign prostatic hyperplasia who underwent simple prostatectomy. Two years after surgery, prostatic biopsies showed atrophy and mild chronic inflammation, with no evidence of malignancy. This unusual intraepithelial lesion seems not to have been described before and may represent a new variant of high grade prostatic intraepithelial neoplasia (HGPIN) with squamous differentiation.

Aged↗
PubMed1997

Risk of concurrent prostate cancer in cystoprostatectomy specimens is related to volume of high-grade prostatic intraepithelial neoplasia.

OBJECTIVES: To assess the relationship of prostatic intraepithelial neoplasia (PIN) with both incidental and clinical carcinoma of the prostate. METHODS: We retrospectively reviewed prostate histology in 48 men (group 1) who underwent surgical removal of the prostate for diagnoses other than prostate cancer, as well as in 64 men (group 2) who underwent radical prostatectomies. Both groups were assessed for the presence and extent of high-grade (HG-) PIN and compared with respect to patient age, Gleason score, and volume of prostate cancer. RESULTS: HG-PIN was present in 40 of 48 (83%) group 1 cases. Forty-six percent of these cases (22 of 48) had incidental prostate cancer. Twenty-nine of 48 (60%) group 1 patients with HG-PIN had multifocal or extensive disease. Twenty of 22 (91%) incidental prostate cancers were present in 29 prostates with multifocal or extensive HG-PIN. In contrast, only 2 of 19 (11%) cases with absent to focal HG-PIN had prostate cancer. The association of multifocal or extensive HG-PIN with incidental prostate cancer was significant (P = 0.001); the relationships of extent of HG-PIN and cancer volume (P = 0.06) or high Gleason score (P = 0.017) were not significant. HG-PIN was present in 61 of 64 (95%) group 2 cases. The associations of extent of HG-PIN and cancer volume (P = 0.169) or high Gleason score (P = 0.156) were not significant. CONCLUSIONS: Both the low rate of incidental prostate cancer in specimens with absent to focal HG-PIN and the high rate of cancer in specimens with multifocal or extensive HG-PIN suggest that HG-PIN is a marker for concurrent prostate cancer and that the risk of concurrent prostate cancer is related to the volume of HG-PIN in the prostate gland.

Aged↗