Long exposure to a mixture of endocrine disruptors prediposes the ventral prostate of rats to preneoplastic lesions.

Endocrine disruptors (ED) are compounds dispersed in the environment that modify hormone biosynthesis, affecting hormone-dependent organs such as the prostate. Studies have only focused on evaluating the effects of ED alone or in small groups and short intervals and have not adequately portrayed human exposure. Therefore, we characterized the prostate histoarchitecture of rats exposed to an ED mixture (ED Mix) mimicking human exposure. Pregnant females of the Sprague-Dawley strain were randomly distributed into two experimental groups: Control group (vehicle: corn oil, by gavage) and ED Mix group: received 32.11 mg/kg/day of the ED mixture diluted in corn oil (2 ml/kg), by gavage, from gestational day 7 (DG7) to post-natal day 21 (DPN21). After weaning at DPN22, the male pups continued to receive the complete DE mixture until they were 220 days old when they were euthanized. The ED Mix decreased the epithelial compartment, increased the fractal dimension, and decreased glandular dilation. In addition, low-grade prostatic intraepithelial neoplasia was observed in addition to regions of epithelial atrophy in the group exposed to the ED Mix. Exposure to the mixture decreased both types I and III collagen area in the stroma. We concluded that the ED Mix was able to cause alterations in the prostatic histoarchitecture and induce the appearance of preneoplastic lesions.

Avaliação de fatores de risco e antígeno prostático específico no rastreamento de câncer de próstata / Evaluation of risk factors and prostate-specific antigen in prostate cancerscreening

Introdução: no Brasil, o câncer de maior incidência nos homens é o câncer de próstata (CaP), com 6,9% de mortalidade. Atualmente, discute-se a aplicabilidade do antígeno prostático específico (PSA) em políticas de rastreamento para CaP e os riscos associados ao sobrediagnóstico. Objetivo: correlacionar a dosagem do PSA com fatores de risco, história clínica e a presença de neoplasia prostática. Metodologia: estudo descritivo transversal que analisou, comparativamente, dados clínico-epidemiológicos e níveis séricos de PSA de 200 pacientes. Valores de PSA foram estratificados em três categorias (<2,5, 2,5­10,0 e >10 ng/ml). Resultados: os fatores de risco analisados foram relacionados significativamente com o aumento do PSA e neoplasia prostática. A prevalência de CaP (11%) e hiperplasia prostática (61%) foi observada nos pacientes com maior dosagem de PSA, enquanto 1% dos pacientes apresentou CaP sem alteração do PSA e 4% tiveram CaP com 2,5­10,0 ng/ml de PSA. Maiores níveis séricos do biomarcador foram relacionados a diabetes (70%), hipertensão (77%), uso crônico de medicações (60%) e ausência de exames periódicos (58%). O grupo com PSA >10 ng/ml teve média de idade maior que o primeiro (p = 0,002) e o segundo grupos (p = 0,027). Conclusão: a prevalência de hiperplasia prostática benigna associada à alteração do PSA, e o elevado risco de exames falso-positivos evidenciam a preocupação com o sobrediagnóstico. No contexto dos dados clinico-epidemiológicos avaliados, a possibilidade de resultados falso-positivos e falso-negativos associados à dosagem do PSA deve ser considerada, ressaltando a importância de adoção de exames complementares para rastreio do CaP.

Introduction: in Brazil, the cancer with the highest incidence in men is prostate cancer (PCa), with 6.9% mortality. Currently, the applicability of prostate specific antigen (PSA) in screening policies for PCa and the risks associated with overdiagnosis are discussed. Objective: to correlate the PSA level with risk factors, clinical history and the presence of prostatic neoplasm. Methods: a cross-sectional descriptive study that analyzed, comparatively, clinical-epidemiological data and serum PSA levels of 200 patients. PSA values were stratified into three categories (<2.5, 2.5­10.0 and> 10 ng / ml). Results: the risk factors analyzed were significantly related to the increase in PSA and prostatic neoplasm. The prevalence of PCa (11%) and prostatic hyperplasia (61%) was observed in patients with higher levels of PSA, while 1% of patients had PCa without PSA changes and 4% had PCa with 2.5­10.0 ng/ml PSA. Increased serum levels of the biomarker were related to diabetes (70%), hypertension (77%), chronic use of medications (60%) and periodic exams (58%). The group with PSA> 10 ng/ml had a mean age greater than the first (p = 0.002) and the second group (p = 0.027). Conclusion: the prevalence of benign prostatic hyperplasia associated with PSA change and an increased risk of false-positive tests show a concern with overdiagnosis. In the context of clinical-epidemiological data, the possibility of false-positive and false-negative results associated with the PSA measurement have to be considered, highlighting the importance of complementary tests for PCa screening.

Chronic prostatitis alters the prostatic microenvironment and accelerates preneoplastic lesions in C57BL/6 mice.

BACKGROUND: Chronic prostatitis has been supposed to be associated with preneoplastic lesions and cancer development. The objective of this study was to examine how chronic inflammation results in a prostatic microenvironment and gene mutation in C57BL/6 mice. METHODS: Immune and bacterial prostatitis mouse models were created through abdominal subcutaneous injection of rat prostate extract protein immunization (EAP group) or transurethral instillation of uropathogenic E. coli 1677 (E. coli group). Prostate histology, serum cytokine level, and genome-wide exome (GWE) sequences were examined 1, 3, and 6 months after immunization or injection. RESULT: In the EAP and E. coli groups, immune cell infiltrations were observed in the first and last months of the entire experiment. After 3 months, obvious proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) were observed accompanied with fibrosis hyperplasia in stroma. The decrease in basal cells (Cytokeratin (CK) 5+/p63+) and the accumulation of luminal epithelial cells (CK8+) in the PIA or PIN area indicated that the basal cells were damaged or transformed into different luminal cells. Hic1, Zfp148, and Mfge8 gene mutations were detected in chronic prostatitis somatic cells. CONCLUSION: Chronic prostatitis induced by prostate extract protein immunization or E. coli infection caused a reactive prostatic inflammation microenvironment and resulted in tissue damage, aberrant atrophy, hyperplasia, and somatic genome mutation.

Chronic prostatitis alters the prostatic microenvironment and accelerates preneoplastic lesions in C57BL/6 mice

BACKGROUND: Chronic prostatitis has been supposed to be associated with preneoplastic lesions and cancer development. The objective of this study was to examine how chronic inflammation results in a prostatic microenvironment and gene mutation in C57BL/6 mice. METHODS: Immune and bacterial prostatitis mouse models were created through abdominal subcutaneous injection of rat prostate extract protein immunization (EAP group) or transurethral instillation of uropathogenic E. coli 1677 (E. coli group). Prostate histology, serum cytokine level, and genome-wide exome (GWE) sequences were examined 1, 3, and 6 months after immunization or injection. RESULT: In the EAP and E. coli groups, immune cell infiltrations were observed in the first and last months of the entire experiment. After 3 months, obvious proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) were observed accompanied with fibrosis hyperplasia in stroma. The decrease in basal cells (Cytokeratin (CK) 5+/p63+) and the accumulation of luminal epithelial cells (CK8+) in the PIA or PIN area indicated that the basal cells were damaged or transformed into different luminal cells. Hic1, Zfp148, and Mfge8 gene mutations were detected in chronic prostatitis somatic cells. CONCLUSION: Chronic prostatitis induced by prostate extract protein immunization or E. coli infection caused a reactive prostatic inflammation microenvironment and resulted in tissue damage, aberrant atrophy, hyperplasia, and somatic genome mutation.

Immunoexpression of cell cycle regulators in canine prostate with proliferative lesions / Imunoexpressão de reguladores do ciclo celular em próstatas caninas com alterações proliferativas

Immunostaining of p21, p27, p53, cyclin D1, c-myc was evaluated in normal canine prostate and prostate with proliferative disorders to verify the interaction between these regulators of cell cycle progression. From 106 samples of canine prostate obtained from a TMA block, 15 were considered normal, 16 diagnosed as benign prostatic hyperplasia (BPH), 30 as proliferative inflammatory atrophy (PIA), 20 as prostatic intraepithelial neoplasia (PIN), and 25 as prostatic carcinoma (PC). There was positive correlation between p21 and p27 for number of stained cells and staining intensity in all conditions and between c-myc and p53 in prostates with PIN. Considering the number of labeled cells, there was positive correlation between p21 and p53 in the normal prostate. Relative to the intensity of staining, there was positive correlation between p21 and p53 in prostate tissue with PIN and between p27 and c-myc in prostates with PIA. A negative correlation between c-myc and cyclin D1 was also identified in the glands with PIN, considering the number of labeled cells, and between p27 and c-myc in the prostates with PC for staining intensity. In conclusion, the expression of p21, p27, p53, cyclin D1 and c-myc varies according to type of proliferative lesion in canine prostate. Taken together, the results indicate low growth potential of the canine PC in the presence of p21 and p27 overexpression, cyclin D1 low expression and regular expression of c-myc, even with the expression of p53 mutant type. Further, it was possible reaffirm the premalignant potential of PIA and PIN in canine prostate.(AU)

A imunomarcação de p21, p27, p53, ciclina D1 e c-myc foi avaliada na próstata canina normal e com desordens proliferativas para verificar quanto a interação desses reguladores na progressão do ciclo celular. Um total de 106 amostras de próstata canina foi obtido a partir de um bloco de TMA, sendo 15 normais, 16 hiperplasia prostática benigna (HPB), 30 atrofia inflamatória proliferativa (PIA), 20 neoplasia intraepitelial prostática (PIN), e 25 carcinoma prostático (PC). Foi encontrada diferença na imunomarcação de p21, p27, ciclina D1 e p53 no epitélio acinar em relação aos diagnósticos. Houve correlação positiva entre p21 e p27 para as variáveis número de células marcadas e intensidade de imunomarcação em todos os diagnósticos (normal, HPB, PIA, PIN e PC), e entre c-myc e p53 nas próstatas com PIN. De acordo com o número de células marcadas, houve correlação positiva entre p21 e p53 na próstata normal. De acordo com a intensidade de imunomarcação houve correlação positiva entre p21 e p53 no tecido prostático com PIN e entre p27 e c-myc em próstatas com PIA. Foi observada correlação negativa entre c-myc e ciclina D1 nas glândulas com PIN, considerando o número de células marcadas, e entre p27 e c-myc na próstata com PC, para a variável intensidade de imunomarcação. Conclui-se que a expressão de p21, p27, p53, ciclina D1 e c-myc varia na próstata canina de acordo com o tipo de lesão proliferativa. Em conjunto, os resultados indicam baixo potencial de crescimento dos carcinomas da próstata canina quando há superexpressão de p21 e de p27, baixa expressão de ciclina D1 e expressão normal de c-myc, mesmo com expressão de p53 tipo mutante. Ainda, considerando o imunofenótipo semelhante nas glândulas com PIA, PIN e PC no que se refere aos reguladores da progressão do ciclo celular, reitera-se o potencial pré-maligno da PIA e PIN na próstata canina.(AU)

The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia

ABSTRACT Purpose We report our experience on metformin use in diabetic patients and its impact on prostate cancer (PCa) after a high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis. Materials and Methods We retrospectively analyzed 551 patients with a diagnosis of HGPIN without PCa in a first prostate biopsy. The cohort of the study consisted of 456 nondiabetic subjects, and 95 diabetic patients. Among the patients with diabetes 44 were treated with metformin, and 51 with other antidiabetic drugs. A transrectal ultrasound prostate biopsy scheme with 22 cores was carried out 4-6 months after the first diagnosis of HGPIN. Results Among 195 (35.4%) patients with cancer, there were statistically significant differences in terms of PCa detection (p<0.001), Gleason score distribution (p<0.001), and number of positive biopsy cores (p<0.002) between metformin users and non-users. Metformin use was associated with a decreased risk of PCa compared with neveruse (p<0.001). Moreover, increasing duration of metformin assumption (≥2 years) was associated with decreasing incidence of PCa and higher Gleason score ≥7 compared with assumption <2 years. Conclusions This preliminary experience suggests that metformin use may have some beneficial effects in patients with diabetes and HGPIN; metformin should not be overlooked in these patients because it is neither new nor expensive.

The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia.

PURPOSE: We report our experience on metformin use in diabetic patients and its impact on prostate cancer (PCa) after a high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis. MATERIALS AND METHODS: We retrospectively analyzed 551 patients with a diagnosis of HGPIN without PCa in a first prostate biopsy. The cohort of the study consisted of 456 nondiabetic subjects, and 95 diabetic patients. Among the patients with diabetes 44 were treated with metformin, and 51 with other antidiabetic drugs. A transrectal ultrasound prostate biopsy scheme with 22 cores was carried out 4-6 months after the first diagnosis of HGPIN. RESULTS: Among 195 (35.4%) patients with cancer, there were statistically significant differences in terms of PCa detection (p<0.001), Gleason score distribution (p<0.001), and number of positive biopsy cores (pv0.002) between metformin users and non-users. Metformin use was associated with a decreased risk of PCa compared with neveruse (p<0.001). Moreover, increasing duration of metformin assumption (≥2 years) was associated with decreasing incidence of PCa and higher Gleason score ≥7 compared with assumption <2 years. CONCLUSIONS: This preliminary experience suggests that metformin use may have some beneficial effects in patients with diabetes and HGPIN; metformin should not be overlooked in these patients because it is neither new nor expensive.

Immunoexpression of cell cycle regulators in canine prostate with proliferative lesions / Imunoexpressão de reguladores do ciclo celular em próstatas caninas com alterações proliferativas

Immunostaining of p21, p27, p53, cyclin D1, c-myc was evaluated in normal canine prostate and prostate with proliferative disorders to verify the interaction between these regulators of cell cycle progression. From 106 samples of canine prostate obtained from a TMA block, 15 were considered normal, 16 diagnosed as benign prostatic hyperplasia (BPH), 30 as proliferative inflammatory atrophy (PIA), 20 as prostatic intraepithelial neoplasia (PIN), and 25 as prostatic carcinoma (PC). There was positive correlation between p21 and p27 for number of stained cells and staining intensity in all conditions and between c-myc and p53 in prostates with PIN. Considering the number of labeled cells, there was positive correlation between p21 and p53 in the normal prostate. Relative to the intensity of staining, there was positive correlation between p21 and p53 in prostate tissue with PIN and between p27 and c-myc in prostates with PIA. A negative correlation between c-myc and cyclin D1 was also identified in the glands with PIN, considering the number of labeled cells, and between p27 and c-myc in the prostates with PC for staining intensity. In conclusion, the expression of p21, p27, p53, cyclin D1 and c-myc varies according to type of proliferative lesion in canine prostate. Taken together, the results indicate low growth potential of the canine PC in the presence of p21 and p27 overexpression, cyclin D1 low expression and regular expression of c-myc, even with the expression of p53 mutant type. Further, it was possible reaffirm the premalignant potential of PIA and PIN in canine prostate.

A imunomarcação de p21, p27, p53, ciclina D1 e c-myc foi avaliada na próstata canina normal e com desordens proliferativas para verificar quanto a interação desses reguladores na progressão do ciclo celular. Um total de 106 amostras de próstata canina foi obtido a partir de um bloco de TMA, sendo 15 normais, 16 hiperplasia prostática benigna (HPB), 30 atrofia inflamatória proliferativa (PIA), 20 neoplasia intraepitelial prostática (PIN), e 25 carcinoma prostático (PC). Foi encontrada diferença na imunomarcação de p21, p27, ciclina D1 e p53 no epitélio acinar em relação aos diagnósticos. Houve correlação positiva entre p21 e p27 para as variáveis número de células marcadas e intensidade de imunomarcação em todos os diagnósticos (normal, HPB, PIA, PIN e PC), e entre c-myc e p53 nas próstatas com PIN. De acordo com o número de células marcadas, houve correlação positiva entre p21 e p53 na próstata normal. De acordo com a intensidade de imunomarcação houve correlação positiva entre p21 e p53 no tecido prostático com PIN e entre p27 e c-myc em próstatas com PIA. Foi observada correlação negativa entre c-myc e ciclina D1 nas glândulas com PIN, considerando o número de células marcadas, e entre p27 e c-myc na próstata com PC, para a variável intensidade de imunomarcação. Conclui-se que a expressão de p21, p27, p53, ciclina D1 e c-myc varia na próstata canina de acordo com o tipo de lesão proliferativa. Em conjunto, os resultados indicam baixo potencial de crescimento dos carcinomas da próstata canina quando há superexpressão de p21 e de p27, baixa expressão de ciclina D1 e expressão normal de c-myc, mesmo com expressão de p53 tipo mutante. Ainda, considerando o imunofenótipo semelhante nas glândulas com PIA, PIN e PC no que se refere aos reguladores da progressão do ciclo celular, reitera-se o potencial pré-maligno da PIA e PIN na próstata canina.

Serum carotenoid and retinol levels in African-Caribbean Tobagonian men with high prostate cancer risk in comparison with African-American men.

Black men are known to have a higher risk for prostate cancer (PC). Carotenoids and retinol, linked to PC, have not been compared in different black populations at risk. We examined serum carotenoid and retinol levels between PC-free African-Caribbean (AC) Tobagonian men with a high PC risk (high-grade prostatic intraepithelial neoplasia, atypical foci or repeated abnormal PC screenings) and African-American (AA) men with elevated serum prostate-specific antigen (PSA) levels (≥4 ng/ml). AC men who participated in the 2003 lycopene clinical trial and AA men who participated in the 2001-2006 National Health and Nutrition Examination Survey were compared. Serum specimens were analysed for carotenoid (ß-carotene, α-carotene, ß-cryptoxanthin, lutein/zeaxanthin and lycopene) and retinol levels by isocratic HPLC. Quantile regression was used to examine the association between serum carotenoid and retinol levels and black ethnicity, overall and among men with elevated serum PSA. There were sixty-nine AC men and sixty-five AA men, aged 41-79 years, included. AC men were associated with lower serum lycopene and retinol levels, and higher serum α- and ß-carotenes and lutein/zeaxanthin levels compared with AA men, after adjusting for age, BMI, ever smoked cigarettes, education and hypertension (P≤0·03). Among men with elevated PSA, serum retinol was no longer statistically significant with ethnicity (P=0·06). Possible differences may be attributed to dietary intake, genetics and/or factors that influence bioavailability of these micronutrients. Prospective studies are warranted that investigate whether these differences in micronutrients between AC Tobagonian and AA men influence PC risk.

ESTANDARIZACIÓN DEL PROTOCOLO PARA LA DETECCIÓN DE LAS FUSIONES TMPRSS2: ERG Y DE LA EXPRESIÓN DE LOS GENES EZH2, SPINK-1 y NKX3.1 EN CÁNCER DE PRÓSTATA (CaP) / Protocol Standardization for Detection of TMPRSS2 Fusions: ERG and Gene Expression of EZH2, SPINK-1 and NKX3.1 in Prostate Cancer (PCa)

En la actualidad no existe una herramienta que permita diferenciar pacientes con cáncer de próstata (CaP) de mal pronóstico de aquellos con enfermedad indolente que sólo requieren un seguimiento controlado de la enfermedad. Debido a la coexistencia de diferentes focos premalignos y malignos en el CaP, el entendimiento sobre el proceso de carcinogénesis requiere de un mejor conocimiento. Actualmente, la heterogeneidad morfológica en CaP es evaluada con la puntuación de Gleason, la cual está fuertemente relacionada con el pronóstico de la enfermedad, sin embargo, esto es insuficiente por lo que se trabaja actualmente en identificación de alteraciones moleculares que permitan identificar subtipos que puedan establecer de manera más precisa el pronóstico del paciente. Este estudio preliminar buscó la estandarización del método de cuantificación en muestras prostáticas de FFPE de la expresión de los transcritos de posibles biomarcadores, como los oncogenes SPINK-1 y EZH2, el supresor tumoral NKX3.1, en conjunto con la determinación de la presencia/ausencia del gen de fusión TMPRSS2:ERG, ya que estos transcritos se encuentran involucrados en aparentes eventos excluyentes de la evolución natural del CaP, que apoyan la posibilidad de una clasificación molecular para esta enfermedad.

At present doesn't exist tool to differentiate patients with prostate cancer (PCa) of poor prognosis of those with indolent disease that only require a controlled monitoring of the disease. Because of the coexistence of different premalignant and malignant foci in CaP, the understanding of the carcinogenesis process requires a better understanding. Currently, the morphological heterogeneity in PCa is evaluated with Gleason score, which is closely related to the prognosis of the disease, but this is insufficient so it is currently to work on identifying molecular alterations to identify subtypes that can establish more precisely the patient's prognosis. This preliminary study aimed to standardization of the method of quantification in prostatic samples of FFPE of expression of transcripts of possible biomarkers, such as the oncogenes, SPINK-1 y EZH2, the tumour suppressor, NKX3.1, together with the determination of the presence/absence of gene fusion, TMPRSS2:ERG, being that these transcripts are involved in apparent exclusive events of the natural evolution of PCa, that support the possibility of a molecular classification for this disease.

How many cores should be taken in a repeat biopsy on patients in whom atypical small acinar proliferation has been identified in an initial transrectal prostate biopsy?

Objective To compare cancer detection rates according to the number of biopsy cores in patients on whom a repeat prostate biopsy was performed for atypical small acinar proliferation (ASAP). Materials and Methods The data of 4950 consecutive patients on whom prostate biopsies were performed were assessed retrospectively. A total of 107 patients were identified as having ASAP following an initial prostate biopsy, and they were included in the study. A six-core prostate biopsy (PBx) was performed on 15 of the 107 patients, 12 PBx on 32 patients, and 20 PBx on 60 patients. Cancer detection rates were compared according to the number of biopsy cores. The localization of the cancer foci was also evaluated. Results The cancer detection rates in patients on whom 6 PBx, 12 PBx, and 20 PBx were performed were 20% (3/15), 31% (10/32), and 58% (35/60), respectively, and a statistically significant difference was found (p = 0.005). When cancer detection rates in patients with total prostate specific antigen (PSA) < 10ng/mL, PSA density ≥ 0.15, normal digital rectal examination, and prostate volume ≥ 55mL were compared according to the number of biopsy cores, a significant difference was identified (p = 0.02, 0.03, 0.006, and 0.04, respectively). Seventy-five percent of the foci where cancer was detected were at the same and/or adjacent sites as the ASAP foci in the initial biopsy, and 54% were identified in contralateral biopsies in which ASAP foci were present. Conclusion As the biopsy core number increases, the cancer detection rate increases significantly in patients on whom a repeat biopsy is performed due to ASAP. The highest cancer rate is found in 20-core repeat biopsies performed equally from all foci. .

Matrix metalloproteinases 2 and 9 expression in canine normal prostate and with proliferative disorders / Expressão de metaloproteinases de matriz 2 e 9 na próstata canina normal e com lesões proliferativas

In this study the expression of metalloproteinases 2 (MMP-2) and 9 (MMP-9) in canine normal prostates and with proliferative disorders was evaluated to verify the role of these enzymes in extracellular matrix remodeling (ECM) and in the tissue invasion process. A total of 355 prostatic samples were obtained, from which 36 (10.1%) were normal prostates, 46 (13.0%) with benign prostatic hyperplasia (BPH), 128 (36.1%) with proliferative inflammatory atrophy (PIA), 74 (20.8%) with prostatic intraepithelial neoplasia (PIN), and 71 (20.0%) with prostatic carcinoma (PC). Difference in cytoplasmic immunohistochemical staining of MMP-2 and MMP-9 between acinar epithelium and periacinar stroma was found regarding the different diagnosis. The correlation between MMP-2 and MMP-9 expression in relation to the number of labeled cells in acinar epithelium and periacinar stroma, as well as to the staining intensity in the periacinar stromal cells was evidenced in canine prostates with PIA. In conclusion, MMP-2 and MMP-9 expression has a variation in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in those with PIA, PIN and PC. Moreover, the inflammatory microenvironment of the PIA has influence in the activity of both enzymes.

Este estudo teve como objetivo avaliar a expressão das metaloproteinases 2 (MMP-2) e 9 (MMP-9) em próstatas caninas normais e com desordens proliferativas, verificando o papel dessas enzimas na remodelação da matriz extracelular (MEC) e no processo de invasão tecidual. Um total de 355 amostras prostáticas foram obtidas, sendo 36 (10,1%) normais, 46 (13,0%) com hiperplasia prostática benigna (HPB), 128 (36,1%) com atrofia inflamatória proliferativa (PIA), 74 (20,8%) com neoplasia intraepitelial prostática (PIN) e 71 (20,0%) com carcinoma prostático (CP). Houve diferença de imunomarcação citoplasmática para MMP-2 e MMP-9 entre o epitélio acinar e o estroma periacinar, quanto aos diferentes diagnósticos. Observou-se correlação entre a expressão de MMP-2 e MMP-9 em relação ao número de células marcadas no epitélio acinar e estroma periacinar, bem como para a intensidade de marcação das células estromais periacinares em próstatas caninas com PIA. Conclui-se que há variação na expressão de MMP-2 e MMP-9 em próstatas caninas de acordo com a lesão, com menor expressão em próstatas caninas normais e com HPB, e maior naquelas com PIA, PIN e CP. Ainda, o microambiente inflamatório na PIA influencia a atividade de ambas as enzimas.

Matrix metalloproteinases 2 and 9 expression in canine normal prostate and with proliferative disorders

In this study the expression of metalloproteinases 2 (MMP-2) and 9 (MMP-9) in canine normal prostates and with proliferative disorders was evaluated to verify the role of these enzymes in extracellular matrix remodeling (ECM) and in the tissue invasion process. A total of 355 prostatic samples were obtained, from which 36 (10.1%) were normal prostates, 46 (13.0%) with benign prostatic hyperplasia (BPH), 128 (36.1%) with proliferative inflammatory atrophy (PIA), 74 (20.8%) with prostatic intraepithelial neoplasia (PIN), and 71 (20.0%) with prostatic carcinoma (PC). Difference in cytoplasmic immunohistochemical staining of MMP-2 and MMP-9 between acinar epithelium and periacinar stroma was found regarding the different diagnosis. The correlation between MMP-2 and MMP-9 expression in relation to the number of labeled cells in acinar epithelium and periacinar stroma, as well as to the staining intensity in the periacinar stromal cells was evidenced in canine prostates with PIA. In conclusion, MMP-2 and MMP-9 expression has a variation in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in those with PIA, PIN and PC. Moreover, the inflammatory microenvironment of the PIA has influence in the activity of both enzymes.

Este estudo teve como objetivo avaliar a expressão das metaloproteinases 2 (MMP-2) e 9 (MMP-9) em próstatas caninas normais e com desordens proliferativas, verificando o papel dessas enzimas na remodelação da matriz extracelular (MEC) e no processo de invasão tecidual. Um total de 355 amostras prostáticas foram obtidas, sendo 36 (10,1%) normais, 46 (13,0%) com hiperplasia prostática benigna (HPB), 128 (36,1%) com atrofia inflamatória proliferativa (PIA), 74 (20,8%) com neoplasia intraepitelial prostática (PIN) e 71 (20,0%) com carcinoma prostático (CP). Houve diferença de imunomarcação citoplasmática para MMP-2 e MMP-9 entre o epitélio acinar e o estroma periacinar, quanto aos diferentes diagnósticos. Observou-se correlação entre a expressão de MMP-2 e MMP-9 em relação ao número de células marcadas no epitélio acinar e estroma periacinar, bem como para a intensidade de marcação das células estromais periacinares em próstatas caninas com PIA. Conclui-se que há variação na expressão de MMP-2 e MMP-9 em próstatas caninas de acordo com a lesão, com menor expressão em próstatas caninas normais e com HPB, e maior naquelas com PIA, PIN e CP. Ainda, o microambiente inflamatório na PIA influencia a atividade de ambas as enzimas.

Matrix metalloproteinases 2 and 9 expression in canine normal prostate and with proliferative disorders

In this study the expression of metalloproteinases 2 (MMP-2) and 9 (MMP-9) in canine normal prostates and with proliferative disorders was evaluated to verify the role of these enzymes in extracellular matrix remodeling (ECM) and in the tissue invasion process. A total of 355 prostatic samples were obtained, from which 36 (10.1%) were normal prostates, 46 (13.0%) with benign prostatic hyperplasia (BPH), 128 (36.1%) with proliferative inflammatory atrophy (PIA), 74 (20.8%) with prostatic intraepithelial neoplasia (PIN), and 71 (20.0%) with prostatic carcinoma (PC). Difference in cytoplasmic immunohistochemical staining of MMP-2 and MMP-9 between acinar epithelium and periacinar stroma was found regarding the different diagnosis. The correlation between MMP-2 and MMP-9 expression in relation to the number of labeled cells in acinar epithelium and periacinar stroma, as well as to the staining intensity in the periacinar stromal cells was evidenced in canine prostates with PIA. In conclusion, MMP-2 and MMP-9 expression has a variation in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in those with PIA, PIN and PC. Moreover, the inflammatory microenvironment of the PIA has influence in the activity of both enzymes.

Este estudo teve como objetivo avaliar a expressão das metaloproteinases 2 (MMP-2) e 9 (MMP-9) em próstatas caninas normais e com desordens proliferativas, verificando o papel dessas enzimas na remodelação da matriz extracelular (MEC) e no processo de invasão tecidual. Um total de 355 amostras prostáticas foram obtidas, sendo 36 (10,1%) normais, 46 (13,0%) com hiperplasia prostática benigna (HPB), 128 (36,1%) com atrofia inflamatória proliferativa (PIA), 74 (20,8%) com neoplasia intraepitelial prostática (PIN) e 71 (20,0%) com carcinoma prostático (CP). Houve diferença de imunomarcação citoplasmática para MMP-2 e MMP-9 entre o epitélio acinar e o estroma periacinar, quanto aos diferentes diagnósticos. Observou-se correlação entre a expressão de MMP-2 e MMP-9 em relação ao número de células marcadas no epitélio acinar e estroma periacinar, bem como para a intensidade de marcação das células estromais periacinares em próstatas caninas com PIA. Conclui-se que há variação na expressão de MMP-2 e MMP-9 em próstatas caninas de acordo com a lesão, com menor expressão em próstatas caninas normais e com HPB, e maior naquelas com PIA, PIN e CP. Ainda, o microambiente inflamatório na PIA influencia a atividade de ambas as enzimas.

Matrix metalloproteinases 2 and 9 expression in canine normal prostate and with proliferative disorders

In this study the expression of metalloproteinases 2 (MMP-2) and 9 (MMP-9) in canine normal prostates and with proliferative disorders was evaluated to verify the role of these enzymes in extracellular matrix remodeling (ECM) and in the tissue invasion process. A total of 355 prostatic samples were obtained, from which 36 (10.1%) were normal prostates, 46 (13.0%) with benign prostatic hyperplasia (BPH), 128 (36.1%) with proliferative inflammatory atrophy (PIA), 74 (20.8%) with prostatic intraepithelial neoplasia (PIN), and 71 (20.0%) with prostatic carcinoma (PC). Difference in cytoplasmic immunohistochemical staining of MMP-2 and MMP-9 between acinar epithelium and periacinar stroma was found regarding the different diagnosis. The correlation between MMP-2 and MMP-9 expression in relation to the number of labeled cells in acinar epithelium and periacinar stroma, as well as to the staining intensity in the periacinar stromal cells was evidenced in canine prostates with PIA. In conclusion, MMP-2 and MMP-9 expression has a variation in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in those with PIA, PIN and PC. Moreover, the inflammatory microenvironment of the PIA has influence in the activity of both enzymes.

Este estudo teve como objetivo avaliar a expressão das metaloproteinases 2 (MMP-2) e 9 (MMP-9) em próstatas caninas normais e com desordens proliferativas, verificando o papel dessas enzimas na remodelação da matriz extracelular (MEC) e no processo de invasão tecidual. Um total de 355 amostras prostáticas foram obtidas, sendo 36 (10,1%) normais, 46 (13,0%) com hiperplasia prostática benigna (HPB), 128 (36,1%) com atrofia inflamatória proliferativa (PIA), 74 (20,8%) com neoplasia intraepitelial prostática (PIN) e 71 (20,0%) com carcinoma prostático (CP). Houve diferença de imunomarcação citoplasmática para MMP-2 e MMP-9 entre o epitélio acinar e o estroma periacinar, quanto aos diferentes diagnósticos. Observou-se correlação entre a expressão de MMP-2 e MMP-9 em relação ao número de células marcadas no epitélio acinar e estroma periacinar, bem como para a intensidade de marcação das células estromais periacinares em próstatas caninas com PIA. Conclui-se que há variação na expressão de MMP-2 e MMP-9 em próstatas caninas de acordo com a lesão, com menor expressão em próstatas caninas normais e com HPB, e maior naquelas com PIA, PIN e CP. Ainda, o microambiente inflamatório na PIA influencia a atividade de ambas as enzimas.

The implication of initial 24-core transrectal prostate biopsy protocol on the detection of significant prostate cancer and high grade prostatic intraepithelial neoplasia

PURPOSE: To assess the diagnostic value of an initial 24-sample transrectal ultrasound guided (TRUS) prostate biopsy protocol compared to the 10-core technique. MATERIALS AND METHODS: We retrospectively reviewed the prostate biopsy database of consecutive men undergoing prostate biopsies under local anesthesia by using the 10 (Group A) and 24 (Group B) protocols. Men were stratified according to biopsy protocol and PSA levels. Exclusion criteria were age = 75 years and PSA > 20 ng/mL. The Mann-Whitney U and Fisher's exact test were used for statistical analysis. RESULTS: Between April 2007 and August 2009, 869 men underwent TRUS prostate biopsies of which 379 were eligible for the study. Group A (10-cores) consisted of 243 (64.11 percent) men and group B (24-cores) included 139 (35.89 percent) men. The overall prostate cancer detection rate was 39.09 percent and 34.55 percent in Group A and B, respectively (p = 0.43). An overall 9.8 percent increase in Gleason 7 detection rate was found in Group B (p = 0.24). The high-grade prostatic intraepithelial neoplasia (HGPIN) detection rate in men with negative initial biopsies was 15.54 percent and 35.55 percent in Group A and B, respectively (p < 0.001). In patients with PSA < 10 ng/mL, the 24-core technique increased Gleason 7 detection rate by 13.4 percent (p = 0.16) and HGPIN by 23.4 percent (p = 0.0008), compared to the 10 core technique. The 24-core technique increased the concordance between needle biopsy and prostatectomy specimen compared to 10-core technique (p < 0.002). CONCLUSIONS: The initial 24-core prostate biopsy protocol did not show any benefit in the detection of prostate cancer compared to the 10-core technique. However, it improved the HGPIN detection and the correlation between biopsy results and radical prostatectomy Gleason score in men with lower PSA levels.

Prostate biopsies containing prostate intraepithelial neoplasia and atypical small acinar proliferation: what to do? / Biópsias prostáticas contendo neoplasia intraepitelial e proliferação acinar atípica: o que fazer?

Objective: The aim of the study was to assess the frequency of high-grade prostate intraepithelial neoplasia and atypical small acinar proliferations on a contemporary series, and their relation to posterior diagnosis of prostate cancer. Methods: A retrospective study was conducted with 6,490 consecutive men submitted to extended prostate biopsies between 2000 and 2005 at a single institution. Of these, 400 men (6.16%) had atypical small acinar proliferation or high-grade prostatic intraepithelial neoplasia, and 43 had at least one follow-up biopsy. Results: The overall incidence of high-grade prostatic intraepithelial neoplasia was 4.6% and 1.4% for atypical small acinar proliferation. High-grade prostatic intraepithelial neoplasia plus atypical small acinar proliferation occurred in 0.11% of men. The detection rates of prostate cancer on repeated biopsies were of 38.5 and 53.6% for high-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation, respectively. All patients with high- grade prostatic intraepithelial neoplasia plus atypical small acinar proliferation who had a repeated biopsy were diagnosed with prostate cancer. There was a higher risk of diagnosing prostate cancer in a site close to previous atypical small acinar proliferation (OR = 5.93; p = 0.015). Conclusions: After high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation finding on extended biopsies, close follow-up is recommended, and repeated biopsies should be done according to clinical data as well. Rebiopsies should be strongly recommended when the association high- grade prostatic intraepithelial neoplasia plus atypical small acinar proliferation is present, or when atypical small acinar proliferation is found only after the second biopsy. Repeated biopsies after an atypical small acinar proliferation finding should be always randomized, but sites of atypical small acinar proliferation should be more extensively sampled.

Objetivo: O objetivo do estudo foi avaliar a frequência de neoplasia intraepitelial prostática de alto grau e de proliferações atípicas de pequenos ácinos em uma série atual, e sua relação com o diagnóstico de câncer de próstata. Métodos: Foi realizado estudo retrospectivo com 6.490 homens submetidos consecutivamente a biópsia estendida de próstata entre 2000 e 2005. Destes, 400 (6,16%) apresentaram proliferações atípicas de pequenos ácinos ou neoplasia intraepitelial prostática de alto grau, e 43 foram submetidos à rebiópsias. Resultados: A incidência de neoplasia intraepitelial prostática de alto grau foi de 4,6% e, de proliferações atípicas de pequenos ácinos, 1,4%. Neoplasia intraepitelial prostática de alto grau mais proliferações atípicas de pequenos ácinos ocorreu em 0,11% dos homens. Detecção de câncer de próstata em rebiópsias ocorreu em 38,5 e 53,6% dos homens com neoplasia intraepitelial prostática de alto grau e proliferações atípicas de pequenos ácinos, respectivamente. Todos os homens com neoplasia intraepitelial prostática de alto grau mais proliferações atípicas de pequenos ácinos apresentaram câncer de próstata em rebiópsias. Observou-se um risco elevado de detecção de câncer de próstata próximo ao local onde ocorreram proliferações atípicas de pequenos ácinos previamente (OR = 5,93; p = 0,015). Conclusões: Após o achado de neoplasia intraepitelial prostática de alto grau ou proliferações atípicas de pequenos ácinos em biópsias estendidas, seguimento cauteloso é recomendado, e rebiópsias devem ser realizadas de acordo com dados clínicos. Rebiópsias são fortemente recomendadas quando há associação da neoplasia intraepitelial prostática de alto grau mais proliferações atípicas de pequenos ácinos, ou quando proliferações atípicas de pequenos ácinos são encontradas a partir da segunda biópsia repetida. Rebiópsias após proliferações atípicas de pequenos ácinos devem ser randomizadas, porém locais onde ocorreu o achado de proliferações atípicas de pequenos ácinos devem ser mais extensivamente representados.

Adenocarcinoma incidental de próstata en resección transuretral por causa benigna: Hospital de San José, julio 2006 a marzo 2008 / Incidental prostatic adenocarcinoma during transurethral resection for a bening cause: San Jose Hospital, july 2006 - march 2008

La resección transuretral de próstata es un procedimiento común para tratar patologías urinarias obstructivas benignas. Al material obtenido se le practica estudio histológico para confirmar la naturaleza benigna, pero en algunos casos se ha encontrado como hallazgo incidental un adenocarcinoma en estadios tempranos. No se sabe con claridad cuánto material debe procesarse o si la cantidad de tejido examinado aumenta la posibilidad de encontrar cáncer. El objetivo de este trabajo es determinar la frecuencia de adenocarcinoma incidental de próstata en pacientes sometidos a RTU por causa benigna. Reune 196 casos de RTU en los que se procesó en una segunda fase todo el tejido restante obtenido, describiendo las variables edad, peso del espécimen, número de láminas procesadas, niveles de PSA y categoría diagnóstica, la cual fue clasificada como negativa para maglinidad, PIN alto de grado y adenocarcinoma de próstata estadios T1a y T1b. Se encontró que la frecuencia de cáncer próstata en pacientes a quienes se les realizó RTU por hiperplasia prostática benigna en el Hospital de San José fue muy baja, dos pacientes de 71 y 80 años, además de otro que corresponde a una neoplasia intraepitelial de alto grado (PIN de AG) con niveles normales de PSA, lo que evidencia que la frecuencia es menor que la reportada en la literatura internacional.

Transurethral resection of the prostate (TURP) is a common procedure performed to treat benign urinary obstruction conditions. The specimen obtained undergoes hystologic work-up to confirm benign nature, but in some cases, an early-stage adenocarcinoma is found incidentally. It is not clearly known how much material must be processed or if the amount of tissue examined increases likelihood of finding cancer. The purpose of this work is to determine the frequency rate of incidental prostatic adenocarcinoma in patients who undergo TURP for a benign cause. It gathers 196 cases of TURP in which all the remaining tissue obtained underwent a second phase work-out, considering variables as age, weight of specimen, number of slides processed, PSA levels and diagnostic category, which was classified as negative for malignancy, high-grade prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma in stages T1a and T1b. It was evidenced that the frequency of prostate cancer in patients who underwent TURP for benign prostatic hyperplasia at the San José Hospital was very low, consisting of two patients 71 and 80 years old, as well as one that corresponds to a high-grade prostatic intraepithelial neoplasia (PIN of AG) with normal PSA levels, which evidences that our frequency rate is smaller than that reported in international literature.

Hallazgos patológicos en 100 biopsias prostáticas por punción y diagnóstico original de benignidad / Histological findings in 100 NEEDLE prostatic biopsies and original diagnosis of benignity

Introduction. Detailed revision of prostate biopsies with benign alterations may show potentially malignant lesions limited to isolated fields, which may be overviewed in routine analysis. Aim. To exam the morphological alterations in patients with suspicious of prostatic carcinoma and benign diagnosis in needle biopsies. Materials and methods. During 2000-2001, one hundred consecutive patients with first prostate biopsy diagnosed as benign were included. Biopsies were performed by sextants or modified sextants technique. Slides were reviewed by two observers with knowledge of original diagnosis and this was accepted or modified in accordance to the findings found during the review. Results. Patients age ranged between 57 and 79 years old. Nine per cent of biopsies originally diagnosed as benign revealed different potentially malignant lesions, which should be noted due to possible association with carcinoma. In this group, there were five biopsies with atypical small acinar proliferation, three with few isolated glands with xanthomatous cytoplasm, and one with scarce atypical cells in the prostatic stroma. In contrast with Caucasian and Afro-American population, frequency of high grade intraepithelial neoplasia in needle biopsy seems to be very low and this lesion was not found in any of the 100 biopsies reviewed. Some lesions that simulate carcinoma, as atypical basal cell hyperplasia, post-atrophic hyperplasia, and adenosis were diagnosed as benign, and there was none false positive result. Conclusions. A small but significant group of the biopsies originally diagnosed as benign lesions, showed atypical lesions in isolated fields that were overlooked in the routine analysis. It is necessary the urologist to ask for a directed review of the biopsies if clinical and laboratory data strongly suggest prostatic carcinoma. Additional histological cuts, immunohistochemical studies and more than one observer may increase the frequency of detection of potentially malignant lesions.

Introducción. La revisión detallada de las biopsias prostáticas consideradas benignas, en ocasiones puede mostrar cambios histológicos con potencial maligno limitadas a campos aislados, que pueden ser pasadas por alto en la interpretación rutinaria. Objetivo. Examinar las alteraciones morfológicas en pacientes con sospecha de carcinoma prostático con diagnóstico de benignidad en biopsias prostáticas por punción. Material y métodos. En el periodo 2000-2001 se incluyeron 100 pacientes consecutivos cuya primera biopsia se interpretó como benigna. Las biopsias fueron por sextantes, o sextantes modificadas. Se revisaron las laminillas por dos observadores con el conocimiento del diagnóstico original y éste se aceptó o modificó de acuerdo con los hallazgos encontrados. Resultados. La edad varió de 57 a 79 años. Nueve de las 100 biopsias diagnosticadas como benignas revelaron alteraciones histológicas potencialmente malignas que debieron anotarse en el reporte de patología por su posible asociación con carcinoma. Éstas incluyeron cinco biopsias con proliferaciones acinares atípicas, tres con glándulas de aspecto xantomatoso en campos aislados y una con escasas células atípicas en el estroma prostático. En contraste con la población caucásica y afroamericana, la frecuencia de neoplasia intraepitelial prostática en biopsias por punción en nuestra población parece ser muy baja y ninguna de las 100 biopsias mostró esta alteración. Algunas lesiones que simulan carcinoma como la hiperplasia atípica de células básales, la hiperplasia postatrófica y la adenosis fueron reconocidas como benignas, y no hubo ningún resultado falso positivo. Conclusiones. Un porcentaje significativo de las biopsias con el diagnóstico original de patología benigna, mostraron en la revisión dirigida lesiones focales que fueron pasadas por alto en la práctica cotidiana, incluidas algunas con potencial maligno. El urólogo debe solicitar una revisión dirigida en búsqueda de lesiones sugestivas de malignidad si los datos clínicos y de laboratorio sugieren fuertemente la posibilidad de carcinoma. En estos casos, los niveles histológicos adicionales, los estudios inmunohistoquímicos y la revisión por más de un observador podrían incrementar la detección de lesiones potencialmente malignas.

Prostatic tissue markers in the dog / iptcadores de tecido prostático no cão

Although prostatic diseases are common in older dogs, diagnosis can be difficult due to the presence of concurrent alterations. The routine evaluation of the prostate is not common in veterinary practice, and thus the diagnosis of prostate disease is often late, and the prognosis very poor. The study of other diagnostic methods, such as prostate tissue markers, can help to improve the success rate of treatments.

As enfermidades prostáticas são comuns em cães idosos, sendo o diagnóstico dificultado pela presença de concomitantes alterações. Contudo, a avaliação rotineira da próstata não é muito comum na prática veterinária. Dessa forma, o diagnóstico é realizado tardiamente e o prognóstico toma-se reservado. O estudo de outros métodos de diagnóstico, como os marcadores de tecido prostático, contribuirá para obtenção de maior sucesso no tratamento.