Incidence Of Prostatic Intraepithelial Neoplasia Research Articles

Evaluation of TURP specimen with special reference to prostatic intraepithelial neoplasia and prostatic cancer using light microscopy and immunohistochemical markers of P63, CK5/6, AMACR (p504s), and PSA

Background: Prostate cancer is the world’s leading cause of cancer and the second cause of cancer-related death in men after lung cancer. The incidence of prostatic carcinoma is increasing with age. Prostate intraepithelial neoplasia can only be diagnosed by histopathological examination of prostate tissue. In practice, small foci of cancer and several morphological mimickers of different Gleason Grades were encountered leading to diagnosing difficulty. To overcome this pitfall, the use of HMW Cytokeratin’s 5 and 6 (CK5/6) or p63 or combination of these two with alpha-methyl acyl- COA-racemase (AMACR) is triple cocktail which is recommended. Aims and Objectives: The objectives of this study were to analyze the histomorphology of various non-neoplastic and neoplastic lesions of the prostate and to know the incidence of prostatic intraepithelial neoplasia in transurethral resection of prostate (TURP) specimen, to assess the usefulness of immunohistochemical analysis with a panel of markers (p63, CK5/6, AMACR [p504s], and prostate-specific antigen [PSA]) to confirm the diagnosis of prostatic intraepithelial neoplasia and prostate cancer, and to differentiate several benign mimickers of prostatic adenocarcinoma. Materials and Methods: It is a prospective study performed for 18 month from January 2020 to June 2021. Thirty TURP specimens were collected in 10% formalin and processed in the department of pathology, MCH, Kolkata. Results: In the present study, benign prostatic hyperplasia formed majority of cases (80%). The presence of AMACR and absence of basal cell specific marker p63 and CK5/6 confirm the presence of prostate cancer. Conclusion: High degree of association of HGPIN with prostatic Carcinoma, it is suggested that these HGPIN patients need close follow-up, observation, and investigation to rule out existence of carcinoma, especially in the peripheral zone.

Incidence of prostatic intraepithelial neoplasia in TURP specimens with special reference to p63 expression in various lesions of prostate

Introduction: Prostate cancer is the second common malignancy in men. Prostatic intraepithelial neoplasia (PIN) is the precursor lesion of prostatic carcinoma. Histopathological examination is necessary to diagnose PIN lesions. Objective: The aim of the study is to determine the incidence of Prostatic intraepithelial neoplasia and to analyse the usefulness of basal cell marker p63 expression in various lesions of prostate. Methods: This is a two-year prospective study of 65 transurethral resection specimens of prostate, carried out in the Department of pathology, Dr B R Ambedkar Medical College, Bangalore. mmunohistochemical marker p63 is used and its expression in various lesions was analysed. Results: Out of 65 cases studied, 4 were inflammatory lesions, 52 were benign prostatic hyperplasia (BPH) and 9 were malignant lesions. Low grade PIN was identified in 8(12.3%) cases of BPH. High grade PIN was seen in 9(13.8%) cases and tufting pattern was the commonest. HGPIN was predominantly associated with adenocarcinoma. p63 was expressed in all the benign glands in BPH and HGPIN. Malignant glands were negative for p63 expression.

Loss of the Tumor Suppressor NKX3.1 in Prostate Cancer Cells is Induced by Prostatitis Related Mitogens

Objective: Prostate carcinoma (PCa) is the leading causes of cancer-related death in elderly men. Although several risk factors for the development of prostate cancer have been identified, the impact of chronic prostatitis is still a matter of debate. A key event of prostate cancer pathogenesis is the decrease of the homeo box protein NKX3.1 in the luminal epithelial cells of the prostate observed in early pre-cancerous lesions. Furthermore, inactivation of Nkx3.1 in a mouse model led to high incidence of prostatic intraepithelial neoplasia (PIN) formation underscoring the importance of NKX3.1 loss. In this study, we aimed to define the impact of diverse cytokines and growth factors known to be expressed during chronic prostatitis on NKX3.1 expression. Methods: We determined the NKX3.1 expression in inflamed areas of prostatectomy specimens by immunohistochemistry. NKX3.1 protein and mRNA levels in cytokine and growth factor stimulated PCa cell lines were determined by western blot and RTqPCR. Transcriptional activity of the androgen receptor (AR) was determined by luciferase reporter assays and impact of the AR on NKX3.1 expression by siRNA mediated AR knock down. Results: Treatment of prostate carcinoma cell lines with epidermal growth factor (EGF) dramatically reduced NKX3.1 protein and mRNA levels, while TNFα or IL-1α had only a moderate effect. Moreover, EGF or a combination of PMA and ionomycin (P+I) also caused diminished levels of the AR. However, while NKX3.1 reduction is observed as early as one hour after stimulation the decrease of AR occurred with a delayed kinetic. We show that P+I-induced NKX3.1 proteolysis is proteasome-dependent and influenced by protein kinase C. Conclusion: In summary, we provide evidences for a crucial role of inflammatory mitogenic factors leading to reduced NKX3.1 and AR levels which might contribute to the initiation of pre-cancerous PIN lesions.

Abstract 3261: Gestational protein malnutrition impairs c-myc and p63 protein expression, increases prostatic intraepithelial neoplasia incidence and prostatitis aggressiveness in adult male offspring subjected to hormonal handling

Abstract Background: Prostate cancer is the second most common cancer diagnosed in men; however its etiology remains unknown. Previous studies have shown that environmental adverse factors, such as maternal nutritional status during pregnancy, can influence fetal development and predispose people to diseases in adult life. The feeding of low-protein diets to pregnant rats result in fetal growth disturbance, androgen/estrogen unbalance and changes in the expression and sensibility of hormone receptors in male offspring. These alterations can promote permanent changes in androgen dependent organs, such as in the prostate. In this sense, we hypothesized that the hormonal unbalance that occurs during aging can lead to an increase in the susceptibility to prostatic disorders. Aim: To evaluate our hypothesis, malnourished male rat offspring were submitted to simultaneous estrogen and testosterone exposure in adulthood, to drive lesions in the rat ventral prostate gland (VP). Methods: 17 week-old Wistar rats (n=48) that received in utero normal protein diet (NP group, AIN93G=17% protein) or low protein diet (RP group, AIN93G modified=6% protein) were given implants with 17β-estradiol plus testosterone administration (NPH and RPH groups) for 17 weeks. The animals were killed at the age of 34 weeks and the VP were excised, weighted and processed for histopathological, immunohistochemical (Ki67, AR, p63, e-caderin, laminin, c-myc and GSTP), biochemical and ultrastructural analysis. Results: Both absolute and relative VP weight from NPH animals were about 30% higher than RPH. Serological data showed that estradiol levels were similar in both groups, but testosterone levels were lower in the RPH male offspring. The steroid hormone exposure in adult life promoted prostate lesions in both RPH and NPH offspring associated with reactive stroma. VP from RPH group exhibited heightened susceptibility to prostatic intraepithelial neoplasia (mainly cribriform and signet ring-cell patterns) and increased the incidence and aggressiveness of prostatitis. In this group, a higher proportion of basal cells, increased proliferation index, lower expression ofthe androgen receptor and increased focus of collagenous micronodules closely associated to epithelial neoplasias were also observed. Conclusion:These observations suggest that maternal protein restriction alters adult prostate response to androgen/estrogen handling and increases susceptibility to prostate diseases. Ethical protocol:CEEA,476/2013 IBB-UNESP; Funding Support: 2009/50204-6 and 2013/09649-0. Citation Format: Jaqueline C. Rinaldi, Sergio Luis Felisbino, Reneè Laufer Amorim, Wellerson Rodrigo Scarano, Wagner José Favaro, Luis Antonio Justulin. Gestational protein malnutrition impairs c-myc and p63 protein expression, increases prostatic intraepithelial neoplasia incidence and prostatitis aggressiveness in adult male offspring subjected to hormonal handling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3261. doi:10.1158/1538-7445.AM2014-3261

High‐Fat Diet Obesity Associated With Insulin Resistance Increases Cell Proliferation, Estrogen Receptor, and PI3K Proteins in Rat Ventral Prostate

In this study, we evaluated the effects of obesity and insulin resistance induced by a high-fat diet on prostate morphophysiology, focusing on cell proliferation, expression of androgen (AR) and estrogen receptors (ER) and proteins of the insulin signaling pathway. Adult male Wistar rats were fed a high-fat diet (20% fat) for 15 weeks, whereas control animals received a balanced diet (4% fat). Both groups were then divided and treated for 2 weeks with 1 mg/kg body weight/day of the aromatase inhibitor letrozole or vehicle only. The ventral prostate was analyzed with immunohistochemical, histopathological, stereological, and Western blotting methods. Obese rats showed insulin resistance, hyperinsulinemia, and reduced plasma testosterone levels. The incidence of prostatic intraepithelial neoplasia (PIN) was 2.7 times higher in obese rats and affected 0.4% of the gland compared with 0.1% PIN areas found in control rats. Obesity doubled cell proliferation in both prostate epithelium and stroma. AR content decreased in the prostate of obese rats and estrogen receptor beta (ERβ) increased in this group. Protein levels of insulin receptor substrate 1 and protein kinase B diminished in the obese group, whereas phosphatidylinositol 3-kinase (PI3K) increased significantly. Most structural changes observed in the prostate of obese rats normalized after letrozole treatment, except for increased stromal cell proliferation and ERβ expression, which might be associated with insulin resistance. This experimental model of obesity and insulin resistance induced by a high-fat diet increases cell proliferation in rat prostate. Such alterations are associated with decreased levels of AR and increased ERβ and PI3K proteins. This change can facilitate the establishment of proliferative lesions in rat prostate.

Exposure to ethinylestradiol during prenatal development and postnatal supplementation with testosterone causes morphophysiological alterations in the prostate of male and female adult gerbils.

Steroids perform significant functions in prostatic development and growth, so that interferences of this equilibrium may predispose the gland to the development of diseases during the life. Embryonic and neonatal exposure to xenoestrogens, many of them with endocrine-disrupting potential, has been related to the induction of disturbances in reproductive system organs. Thus, this study aimed to analyse morphological and immunocytochemical aspects of prostate in both male and female adult gerbils either exposed to ethinylestradiol during the prenatal phase (pregnant females received 10 μg/kg, by gavage) (EE group) or exposed to testosterone (1 mg/kg) during the postnatal period (EE/T group). Serological analysis revealed a rise in estradiol levels in adult males and females of the EE group. A higher incidence of prostatic intraepithelial neoplasia (PIN) was observed in the male and female prostate of the treated groups, besides an increase in collagen and reticular fibres. Immunocytochemistry showed an increase in prostatic epithelial cells immunoreactive to AR and a presence of a smooth muscle layer, evidenced by α actin, in injured regions this way absent in prostatic epithelial buds. These pieces of evidence suggest that the alterations verified in the prostate in adulthood of both sexes may be due to the high oestrogen levels. Either males or females of the EE/T group showed normalized estradiol levels, although prostatic lesions could be observed. While the prostatic gland of male gerbils was more affected than the female prostate, this study showed that the exposure to EE during this critical period of development disrupts the prostate of both sexes in terms of prostatic lesions.

Abstract 950: Energy deprivation by Inositol Hexaphosphate inhibits prostate tumor growth and progression in TRAMP mice

Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated deaths in elderly males in Western world, suggesting that newer approaches are needed to prevent/control PCa. Herein, for the first time, by employing anatomical and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), we evaluated non-invasively, the in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high fiber diets, against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The study was conducted on a longitudinal basis to simultaneously assess both prostate sizes and changes in tumor vascularization (perfusion and permeability) due to IP6 feeding. Male TRAMP mice, beginning 4 weeks of age, were fed with 1, 2 or 4% (w/v) IP6 in drinking water or only drinking water till 28 weeks of age and monitored using MRI over the course of treatment. Longitudinal assessment of volumes of prostate and seminal vesicles showed profound effect of 2% and 4% IP6 doses on selectively reducing prostate volume without noticeable changes in seminal vesicles. Further, gadolinium-based DCE-MRI showed decreased tumor perfusion and permeability, indicative of anti-angiogenic effects of IP6 treatment. Histopathological analysis at the end of the study corroborated the MRI results, and showed that IP6-fed mice had less severe prostatic lesions compared to positive controls. Specifically, the mice in IP6-fed groups showed higher incidence of prostatic intraepithelial neoplasia (PIN) at the expense of a strong decrease in adenocarcinoma incidence. Importantly, the mice in IP6-fed groups also had prostatic regions with typical normal histology, which was totally absent in positive controls. IHC and WB results indicated anti-proliferative, pro-apoptotic, and anti-angiogenic effect of IP6 feeding, as evidenced by decreased number of PCNA-, PECAM-1/CD-31-, VEGF- and iNOS- positive cells, together with increased number of TUNEL positive cells. As potential mechanisms of IP6 efficacy, decrease in the expression of glucose transporter (GLUT) proteins together with an increase in phosphorylated levels of AMP-activated kinase (AMPKTh172) and acetyl-CoA carboxylase (ACCSer79) were observed in the prostatic tissue of mice from IP6 fed-groups. Since phosphorylation results in decreased activity of ACC which is an essential enzyme for fatty acid synthesis, our findings suggest that IP6 is interfering with the metabolic events occurring in TRAMP prostate tumor tissue. Together, these findings show that oral IP6 feeding blocks PCa growth and progression in TRAMP mouse model via modulation of metabolic events involved in tumor sustenance and thereby results in energy deprivation within the tumor, suggesting its practical and translational potential in suppressing growth and progression of PCa in humans (NCI RO1 grant CA116636). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 950.

Dietary Feeding of Silibinin Inhibits Prostate Tumor Growth and Progression in Transgenic Adenocarcinoma of the Mouse Prostate Model

Herein, for the first time, we evaluated the chemopreventive efficacy of dietary silibinin against prostate cancer (PCa) growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice from two different genetic backgrounds [C57BL/6 (TRAMP) x FVB; C57BL/6 (TRAMP) x C57BL/6]. At 4 weeks of age, mice were fed control or 0.1% to 1% silibinin-supplemented diets until 23 to 24 weeks of age. Silibinin-fed groups had a lower tumor grade and higher incidence of prostatic intraepithelial neoplasia (PIN) at the expense of a strong decrease in adenocarcinoma incidence. Prostate tissue showed a 47% (P < 0.001) decrease in proliferating cell nuclear antigen (PCNA)-positive cells and an approximately 7-fold (P < 0.001) increase in apoptotic cells at the highest silibinin dose. As potential mechanisms of silibinin efficacy, an approximately 50% (P < 0.05) decrease in insulin-like growth factor (IGF) receptor type I beta and an approximately 13-fold (P < 0.001) increase in IGF-binding protein 3 (IGFBP-3) protein levels were also observed. These changes were specific to tumors as they were not reflected in circulating IGF-IGFBP-3 system. Additionally, silibinin decreased protein expression of cyclin-dependent kinases (Cdk) by more than 90% (P < 0.001) with a concomitant increase in Cdk inhibitors, Cip1/p21 and Kip1/p27 (P < 0.05, for both). A dose-dependent decrease was also observed in cyclin B1, cyclin E, and cyclin A protein levels by silibinin. Together, these findings suggest that oral silibinin blocks PCa growth and progression at PIN stage in TRAMP mice via modulation of tumor IGF-IGFBP-3 axis and cell cycle regulation, and therefore it has practical and translational potential in suppressing growth and neoplastic conversion of PIN to PCa in humans.

Exisulind in Combination with Celecoxib Modulates Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Cyclin D1 against Prostate Carcinogenesis:In vivoEvidence

Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer. We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays. The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination. In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.

Oral Grape Seed Extract Inhibits Prostate Tumor Growth and Progression in TRAMP Mice

Prostate cancer chemoprevention is an alternative and potential strategy to control this malignancy. Herein, we evaluated the chemopreventive efficacy of grape seed extract (GSE) against prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice where animals were fed with GSE by oral gavage at 200 mg/kg body weight dose during 4 to 28 weeks of age. Our results showed a significant reduction (46%, P < 0.01) in the weight of genitourinary tract organs in the GSE-fed mice. The GSE-fed group of mice had a higher incidence of prostatic intraepithelial neoplasia but showed strong reduction in the incidence of adenocarcinoma compared with mice in control group. Prostate tissue from the GSE group showed approximately 50% (P < 0.001) decrease in proliferating cell nuclear antigen (PCNA)-positive cells and 64% (P < 0.01) reduction in total PCNA protein level compared with the control group; however, GSE increased apoptotic cells by 8-fold. Furthermore, GSE strongly decreased the protein levels of cyclin B1, cyclin A, and cyclin E by 84% (P < 0.05), 96% (P < 0.05), and 89% (P < 0.001), respectively. The protein expression of cyclin-dependent kinases 2 and 6 and Cdc2 was also decreased by more than 90% (P < 0.05) in the prostate from the GSE-fed group. Together, for the first time, we identified that oral GSE inhibits prostate cancer growth and progression in TRAMP mice, which could be mediated via a strong suppression of cell cycle progression and cell proliferation and an increase in apoptosis.

Atrophy in prostate needle biopsy cores and its relationship to prostate cancer incidence in screened men

Objectives To evaluate whether the incidence of atrophy reported on sextant biopsies is associated with subsequent prostate cancer detection and to obtain a more thorough analysis of the different categories and extent of atrophy, we performed a review of benign biopsy cores. Methods In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, 4117 and 1840 men underwent sextant biopsy in the first and second screening round (4-year interval), respectively. Sextant biopsy was prompted by elevated prostate-specific antigen levels. For review, randomly taken benign sextant biopsies (n = 202) with a follow-up of at least 8 years were chosen. Results Before review, atrophy was reported in the biopsies of 11.4% and 8.7% of the first and second round, respectively. The prostate cancer incidence during 8 years of follow-up after an initial diagnosis of atrophy was 10.4%, which was not significantly different than the 12.3% of cancers detected after a benign diagnosis without reference to atrophy. After review, the incidence of simple atrophy, post-atrophic hyperplasia, and sclerotic atrophy in sextant biopsies was 91%, 47%, and 9%, respectively. Extensive atrophy was observed in 5% of biopsies. Only 2 men (4.7%) in the reviewed group had a subsequent diagnosis of prostate cancer in the 8 years of follow-up. Additionally, prostatic intraepithelial neoplasia was diagnosed in 3 men (7.0%) in the second screening round. Conclusions Atrophy, especially its simple form, is a very common lesion in prostate biopsy cores (94%). Atrophy in an asymptomatic population undergoing screening was not associated with a greater prostate cancer or prostatic intraepithelial neoplasia incidence during subsequent screening rounds.

Estrogen receptor alpha and imprinting of the neonatal mouse ventral prostate by estrogen.

Exposure to estrogen in the neonatal period affects prostatic growth and leads to an increased incidence of prostatic intraepithelial neoplasia in later life. The effects of neonatal estrogen are clearly dependent on estrogen receptor (ER) alpha because they do not occur in ERalpha-knockout mice. Because ERalpha is expressed in the stroma, but not in the epithelium, of the adult ventral prostate, the concept of indirect estrogen effects through stromal signaling has been proposed. Here, we show that during the first 4 weeks of life, there are profound and rapid changes in the ER profile in the mouse ventral prostate. ERalpha is abundant in the stroma during week 1, but by week 2 it is exclusively epithelial, and then by week 4, ERalpha is lost and ERbeta is dominant in the prostatic epithelium. The presence of ERalpha is associated with a high proliferation index, and ERbeta is associated with quiescence. Branching morphogenesis was altered in ERalpha-/-, but not in ERbeta-/-, mice. We conclude that imprinting and branching morphogenesis of the ventral prostate are mediated by estrogen acting directly on epithelial and stromal ERalpha during the first 2 weeks of life.

Beef tallow, but not perilla or corn oil, promotion of rat prostate and intestinal carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl.

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2‐dimethyl‐4‐aminobiphenyl (DMAB) were investigated. Non‐invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg/kg body weight of DMAB at 2‐week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non‐carcinogen‐treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P<0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMAB + TP (from 70 to 10%, P<0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5‐bromo‐2‐deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.

The critical role of patient follow-up after receiving a diagnosis of prostatic intraepithelial neoplasia.

With the increasing incidence of prostatic intraepithelial neoplasia being found at the time of prostate biopsy and the association of prostatic intraepithelial neoplasia to coexisting prostate cancer and/or the future development of prostate cancer, patient compliance in following post-biopsy follow-up instructions for re-biopsy is becoming more significant in the detection of prostate cancer at an earlier and, therefore, potentially curable stage. During a 3-y period, we reviewed the charts of 130 patients who received an initial diagnosis of prostatic intraepithelial neoplasia after undergoing transrectal ultrasound of the prostate with biopsy. It is our policy to inform the patient of their diagnosis of prostatic intraepithelial neoplasia at the time of the initial biopsy and to recommend a repeat biopsy in 6-12 months. Patients are informed of the diagnosis of prostatic intraepithelial neoplasia verbally and in writing. In addition, a letter is sent to their referring physician with the re-biopsy recommendation. Thirty-nine of 130 patients (30%) were seen for re-biopsy within the specified time. An additional 36 patients (27.69%) were re-biopsied between 12 and 18 months after the initial diagnosis of prostatic intraepithelial neoplasia. An additional 11 patients (7%) were re-biopsied more than 18 months after their initial diagnosis. Forty-four patients failed to return for re-biopsy. Overall, patient follow-up within the desired protocol was poor and must be improved upon to prevent any delays in the diagnosis of prostate cancer. Prostate Cancer and Prostatic Diseases (2001) 4, 63-66

EFFECT OF NEOADJUVANT HORMONAL THERAPY ON PROSTATIC INTRAEPITHELIAL NEOPLASIA AND ITS PROGNOSTIC SIGNIFICANCE

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

Incidence of prostatic intra-epithelial neoplasia in Osaka, Japan.

High-grade prostatic intra-epithelial neoplasia (HGPIN) is the most likely precancerous lesion for prostatic carcinoma. A high incidence of its association with cancer has been reported in Western countries. On the other hand, information regarding its incidence is limited in Japan, where the mortality due to prostate cancer is much lower. We reviewed 53 clinical stage T2 or T3 prostatic cancers of Japanese patients living in Osaka, Japan (mean age, 67.2 years). These cases were subdivided into a pre-operatively non-castrated group (34 cases) and a medically or surgically castrated group (19 cases). HGPIN was found in 27 cases. The incidence of HGPIN was significantly lower in the castrated group (21.0%) compared with the non-castrated group (67.6%). In the non-castrated group, patient age, pathological stage, Gleason score, tumor size and serum prostate-specific antigen showed no significant correlation with HGPIN. Advanced pathological stage and tumor size tended to decrease the incidence of HGPIN, although this was not statistically significant. When the study group was limited to stage T2 tumors of the non-castrated group, the incidence of HGPIN was 81.0%. HGPIN in Japan may also be clinically and etiologically significant as a precursor of clinical cancer.

The Incidence of High Grade Prostatic Intraepithelial Neoplasia in Needle Biopsies

Purpose High grade prostatic intraepithelial neoplasia is the most likely precursor of invasive prostate cancer. The identification of prostatic intraepithelial neoplasia in needle biopsy specimens warrants repeat biopsy because of its high predictive value for cancer. The incidence of prostatic intraepithelial neoplasia in contemporary needle biopsies is unknown. Materials and Methods To determine the incidence of patients requiring repeat needle biopsy because of abnormal findings in needle aspirations (high grade prostatic intraepithelial neoplasia and microscopic foci suspicious for but not diagnostic of malignancy), we compared the pathological findings in 400 prostatic needle biopsies, including 200 consecutive cases from an academic medical center (Mayo Clinic) and an equal number from a private practice laboratory (Glendale Memorial Hospital and Health Center). Results The biopsies revealed similar findings from the 2 medical centers: benign prostatic tissue in 41.5 to 50 percent of the cases, prostatic intraepithelial neoplasia in 16.5 to 9.5 percent, foci suspicious for but not diagnostic of malignancy in 1.5 to 2.5 percent and cancer in 40.5 to 38 percent (Mayo Clinic versus Glendale Memorial, respectively). Clinical information was available from the 200 Mayo Clinic patients who underwent biopsy, and there was no difference in the distribution of findings by digital rectal examination or transrectal ultrasound, although the median serum prostate specific antigen concentration was higher in patients with prostatic intraepithelial neoplasia and cancer than in those with benign biopsies. Conclusions High grade prostatic intraepithelial neoplasia is a frequent finding in needle biopsies and is present in up to 16.5 percent of the cases. There was no apparent difference in the incidence of prostatic intraepithelial neoplasia and cancer between 2 geographically diverse medical centers. Up to 18 percent of patients are candidates for another biopsy based on needle biopsy findings of prostatic intraepithelial neoplasia or foci suspicious for but not diagnostic of malignancy.