The TNM 8th edition: Validation of the proposal for organ - confined (pT2) prostate cancer

ABSTRACT Purpose: The 8th edition of the TNM has been updated and improved in order to ensure a high degree of clinical relevance. A major change in prostate includes pathologically organ - confined disease to be considered pT2 and no longer subclassified by extent of involvement or laterality. The aim of this study was to validate this major change. Materials and Methods: Prostates were step - sectioned from 196 patients submitted to radical prostatectomy with organ confined disease (pT2) and negative surgical margins. Tumor extent was evaluated by a semiquantitative point count method. The dominant nodule extent was recorded as the maximal number of positive points of the largest single focus of cancer from the quadrants. Laterality was considered as either total tumor extent (Group 1) or index tumor extent (Group 2). Time to biochemical recurrence was analyzed with the Kaplan - Meier product limit analysis and prediction of shorter time to biochemical recurrence with Cox proportional hazards model. Results: In Group 1, 43 / 196 (21.9%) tumors were unilateral and 153 / 196 (78.1%) bilateral and in Group 2, 156 / 196 (79.6%) tumors were unilateral and 40 / 196 (20.4%) bilateral. In both groups, comparing unilateral vs bilateral tumors, there was no significant clinicopathological difference, and no significant association with time as well as prediction of shorter time to biochemical recurrence following surgery. Conclusions: Pathologic sub - staging of organ confined disease does not convey prognostic information either considering laterality as total tumor extent or index tumor extent. Furthermore, no correlation exists between digital rectal examination and pathologic stage.

High cancer detection rate using cognitive fusion - targeted transperineal prostate biopsies

ABSTRACT Objective MRI of the prostate improves diagnostic accuracy of prostate cancer. Different fusion approaches with transrectal ultrasound images are employed. Objective To determine detection rate of prostate cancer in men undergoing transperineal MRI-based cognitive fusion biopsy. Materials and Methods One hundred and sixty-four consecutive men underwent a multiple-core prostate transperineal biopsy. Univariable and multivariable logistic regression analyses were used to address the relationship between clinical parameters and prostate cancer detection rate. Results One hundred and fourteen patients underwent mpMRI prior to the transperineal biopsy, 52 (45%) were diagnosed with prostate cancer, of them, 36 had Gleason score ≥7 (69%). Among these 114 patients, 82 had suspicious lesions on MRI, and 43 of them were diagnosed with cancer (52%). On multivariate analysis, the most significant independent predictive factors were PSA density (P<0.001) and suspicious MRI lesion (P=0.006). Men with a PSA density of more than 0.22 and a suspicious lesion on MRI had a detection rate of 78%. Detection rate among 50 patients with no MRI study prior to this biopsy was 26%. Conclusions This study showed that among a group of mostly multi-biopsied patients, the presence of mpMRI lesions and high PSA density values helped to detect clinically significant prostate cancer using cognitive MRI/TRUS fusion biopsies.

Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

Introduction and objective: Overexpression of MMPs has been related to biochemical recurrence after radical prostatectomy. TIMP1 and TIMP2 are controllers of MMPs and the aim of this study is to evaluate the expression levels of MMPs and their regulators using immunohistochemistry in tissue microarray of localized prostate cancer (PC). Materials and Methods: Immune-expression of MMP-9, MMP-2, TIMP1, TIMP-2, MMP-14 and IL8, were analyzed by immunohistochemistry in radical prostatectomy specimens of 40 patients with localized PC who underwent surgery between September 1997 and February 2000. Protein expression was considered as categorical variables, negative or positive. The results of the immune-expression were correlated to Gleason score (GS), pathological stage (TNM), pre-operatory PSA serum levels and biochemical recurrence in a mean follow up period of 92.5 months. Results: The loss of TIMP1 immune-expression was related to biochemical recurrence. When TIMP1 was negative, 56.3% patients recurred versus 22.2% of those whose TIMP1 was positive (p=0.042). MMP-9, MMP-2, IL8 and MMP-14 were positive in the majority of PC. TIMP-2 was negative in all cases. Conclusion: Negative immune-expression of TIMP1 is correlated with biochemical recurrence in patients with PC possibly by failing to control MMP-9, an important MMP related to cancer progression.

Characterization of reactive stroma in prostate cancer: involvement of growth factors, metalloproteinase matrix, sexual hormones receptors and prostatic stem cells

ABSTRACT Introduction and Objectives: Reactive Stroma (RStr) is observed in many human cancers and is related to carcinogenesis. The objectives of the present study were to stablish a relationship of the RStr microenvironment with prostate cancer (Pca) through a morphological and molecular characterization, and to identify a possible relationship between RStr with worse prognosis factors and occurrence of malignant prostatic stem cells. Materials and Methods: Forty prostatic samples were selected from men with Pca diagnosis submitted to radical prostatectomy; they were divided in two groups: Group-1 (n=20): samples without reactive stroma; Group-2 (n=20): samples of PCa with intense stroma reaction. Prostatic samples were evaluated for RStr intensity by Masson Trichromic stain and posteriorly submitted to histopathological and immunohistochemistry analysis for antigens: α-actin, vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA, AR, Erα and ERβ. Results: Reactive stroma with intense desmoplastic reactivity was significantly more frequent in intermediate (Gleason 7, 3+4) and high grade tumors (Gleason 7, 4+3). The group with intense stromal reactivity showed significant higher levels of Vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA and ERα. Conclusions: It can be concluded that RStr may be a predictive marker of Pca progression, since it was associated with increase of growth factors, imbalance of androgen and estrogen receptors and presence of malign prostatic stem cells.

Correlation between Beta1 integrin expression and prognosis in clinically localized prostate cancer

Integrins are transmembrane glycoprotein receptors that regulate cell-matrix interactions, thus functioning as sensors from the environment. They also act as cell adhesion molecules that are responsible for the maintenance of the normal epithelial phenotype. Some studies have reported a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, however its role in prostate cancer (PC) is unclear. The aim of our study was to evaluate the expression of β1 integrin in localized PC and to correlate the pattern of expression with recurrence after surgical treatment. Methods For this case-control study, we retrospectively selected surgical specimens from 111 patients with localized PC who underwent radical prostatectomy. Recurrence was defined as a PSA level exceeding 0.2ng/mL after surgery, and the median follow-up was 123 months. Integrin expression was evaluated by immunohistochemistry in a tissue microarray containing two samples from each tumor. We employed a semiquantitative analysis and considered a case as positive when the expression was strong and diffusely present. Results: There was a loss of 11 cases during the tissue micro array assembling. β1 expression was positive in 79 of the 100 evaluated cases (79%). The univariate and multivariate analyses showed that the negative expression of β1 integrin was associated with biochemical recurrence (p = 0.047) and time to recurrence after radical prostatectomy (p = 0.023). When β1 was negative, the odds ratio for recurrence was 2.78 times higher than that observed in the positive cases [OR = 2.78, p = 0.047, IC 95% (1.01-7.66)]. Conclusions: The loss of β1 integrin immune expression was correlated with biochemical recurrence in patients treated with radical prostatectomy for localized PC.

Identificación de factor de crecimiento vascular endotelial en células glandulares de tejido prostético maligno y benigno: Relación con la recidiva tumoral al año de la prostatectomía / Vascular endothelial growth factor in malignant and non malignant prostatic tissue: Association with tumor recurrence at one year after prostatectomy

Background: Prostate cancer (PC) is the second cause of death by cancer in men in Chile. Its behavior is so variable that it is necessary to search reliable prognostic markers. Vascular Endothelial Growth Factor (VEGF) is one of the most powerful pro-angiogenic factors. There is no agreement on its validity as a diagnostic or prognostic factor. Aim: To search for VEFG in prostatic tissue. Material and Methods: This study was performed in prostatectomy tissue coming from 41 patients with PC and 39 patients with benign prostatic hyperplasia (BPH). Specimens were studied using immunohistochemical staining for VEGF. The percentage of stained glandular cells per patient was calculated and associated with pathological diagnosis in cancer patients. Results: PC biopsies had a mean of 82% of VEGF (+) stained cells, while BPH had only 1.6% (p < 0.01). No relationship was found between the percentage of staining and recurrence at one year of follow-up in the case of PC. Conclusions: These results would rule out VEGF as a prognostic factor in this series of patients.

Parallel determination of NeuroD1, Chromogranin-A, KI67 and androgen receptor expression in surgically treated prostate cancers

PURPOSE: Neuroendocrine differentiation is a hallmark of prostate cancer. The aim of our study was the detection of the parallel expression of neuroendocrine related markers using a prostate tissue microarray (TMA). MATERIALS AND METHODS: Our study was aimed at detecting the parallel expression of NeuroD1, Chromogranin-A (ChrA), Androgen Receptor (AR) and Ki-67 by immunohistochemistry on prostate cancer tissue microarray. The data was analyzed using SAS version 8.2 (SAS Inc, Cary, NC). The relationships between NeuroD1, ChrA and AR expressions and patients' characteristics were investigated by multivariate logistic regression analysis. Progression and Overall Survival (OS) distributions were calculated using Kaplan-Meier method. RESULTS: Tissue reactivity for NeuroD1, ChrA and AR concerned 73 percent, 49 percent and 77 percent of the available cases, respectively. Regarding overall survival, there were 87 deaths and 295 patients alive/censored (6 years of median follow-up). Seventy-seven disease progressions occurred at the median follow-up 5.4y. A significant correlation between NeuroD1, ChrA and AR expression was observed (p < 0.001 and p < 0.03, respectively). Additionally, ChrA was strongly associated in multivariate analysis to Gleason score and Ki67 expression (p < 0.009 and p < 0.0052, respectively). Survival analysis showed no association between markers neither for overall nor for cancer-specific survival. CONCLUSIONS: The results highlight that NeuroD1, Chromogranin-A and Androgen Receptor are strongly associated, however their expression does not correlate with overall survival or disease progression.

Expressão imunohistoquímica do marcador tumoral CD34 e P27 como fator prognóstico em adenocarcinoma de próstata clinicamente localizado após prostatectomia radical / Immunohistochemistry expression of tumor markers CD34 and P27 as a prognostic factor of clinically localized prostate adenocarcinoma after radical prostatectomy

OBJETIVO: Analisar a expressão imunoistoquímica do marcador CD34 e p27, como fator prognóstico em pacientes com neoplasia de próstata localizada. MÉTODOS: Análise de 100 casos de pacientes portadores de neoplasia prostática localizada submetida à cirurgia curativa. Realizou-se o preparo histológico habitual, seguido da reação imunoistoquímica para a detecção do acúmulo da proteína CD34 e p27 seguida de análise estatística. RESULTADOS: Na avaliação do marcador P27 e na correlação com as variáveis, observou-se diferença significativa no escore de Gleason com expressão positiva (P27 positivo) relacionada com PSA médio mais baixo (p=0,091), escore de Gleason mais baixo (p<0,0001) e menor área de tumor no CD34 (p=0,036). Correlacionando-se o marcador CD34 na área tumoral observou-se quanto menor o CD34 positivo menor é o valor do PSA (p<0,0001), e menor é o escore de Gleason (r=0,5726 ; p<0,0001) e quanto maior o CD34 positivo maior é o estadiamento (r=0,3305 ; p<0,0001) e a chance de recidiva (p=0,002). Os pacientes com estadiamento mais alto, também tinham maior área CD34 positivo (p<0,0001). CONCLUSÃO: Os marcadores P27 e CD34 estão associados com os eventos próprios ao câncer de próstata; contudo, apenas o CD34 foi capaz de determinar a possibilidade de recidiva bioquímica.

OBJECTIVE: to analyze the immunohistochemical expression of P27 and CD34 markers as prognostic factors in patients with localized prostate cancer. METHODS: analysis of 100 patients with localized prostate cancer submitted to curative surgery. We carried out the usual histological preparation, followed by immunohistochemistry to detect the accumulation of P27 and CD34 protein followed by statistical analysis. RESULTS: in the evaluation of P27 marker and on the correlation with the variables we found significant difference in Gleason score with positive expression (positive P27) related to lower mean PSA (p = 0.091), lower Gleason score (p < 0.0001) and smaller tumor area in CD34 (p = 0.036). Regarding the CD34 marker at the tumor area, it was observed that the smaller the positive CD34, the lower the PSA value (p < 0.0001) and lower the Gleason score (r = 0.5726, p < 0.0001), and the higher the positive CD34, the higher the staging (r = 0.3305, p <0.0001) and the chance of recurrence (p = 0.002). Patients with higher stage also displayed larger positive CD34 areas (p < 0.0001). CONCLUSION: the markers CD34 and P27 are associated with events specific to prostate cancer, however, only CD34 was able to determine the possibility of biochemical recurrence.

Expressão da CASPASE-3 e CD-34 no adenocarcinoma de próstata / CASPASE-3 and CD-34 expression in prostate adenocarcinoma

OBJETIVO: 1. Avaliar em qual percentual as células tumorais se marcam com caspase-3 e CD-34; 2. quantificá-los nas células tumorais; 3. verificar correlação entre quantificação e grau de malignidade tumoral; 4. correlacioná-los entre si. MÉTODOS: Estudaram-se 38 blocos com adenocarcinoma, classificados por Gleason e marcação imunoistoquímica para caspase-3 e CD-34. As proteínas imunomarcadas foram quantificadas no software Immuno do Sistema Samba 4000 de citofotometria de imagem, pelo índice de marcagem e densidade óptica. RESULTADOS: Imunomarcou-se 25 lâminas para caspase-3 e 34 para CD-34. As quantificações da caspase-3 para o índice de marcagem foram acima de 50 em 76 por cento e, para densidade óptica, abaixo de 50 para 96 por cento. Em relação ao CD-34, índice de marcagem foi acima de 50 em 59 por cento e densidade óptica abaixo de 50 em 56 por cento. As correlações entre expressões dos marcadores e a gravidade do tumor, assim como entre os marcadores, não evidenciaram significância estatística. Não se mostrou relação de expressão com o score de Gleason. CONCLUSÃO: A presença caspase-3 e CD-34 foi de 73,5 por cento e 100 por cento, respectivamente; 2. caspase-3 e CD-34 apresentaram alta expressão do índice de marcagem, e baixa para densidade óptica; 3. não houve correlação entre as quantificações com a classificação de Gleason; 4. não houve correlação das expressões dos dois marcadores entre si.

OBJCTIVE: 1. To evaluate the percentage of caspase-3 and CD-34 expression on adenocarcinoma; 2. to quantify caspase-3 and CD-34 in tumor cells; 3. to verify the relationship between biomarkers and its malignancy; 4. to correlate biomarkers themselves. METHODS: Thirty-eight human malignant prostate specimens, Gleason's score, were immunohistochemically stained for caspase-3 and CD-34 protein. Quantification was done under Samba 4000 Immuno System reading, yielding two variables: label index and optical density. Statistical analyses were based on cross-methods involving univariate and bivariate as well as correlation factors among independent variables. RESULTS: Immunostaining was revealed in 25 plates for caspase-3 and 34 for CD-34. Caspase-3 expression for label index was over 50 in 76 percent, while for optical density was below 50 in 96 percent. CD-34 expression demonstrated label index over 50 in 59 percent and optical density below 50 in 56 percent. Correlation among expression and severity did not demonstrate to be statistically significant. There was no correlation between protein expression and Gleason's score. CONCLUSION: 1. Caspase-3 and CD-34 were present respectively in 73.5 percent and 100 percent of samples; 2. caspase-3 and CD-34 showed high expression regarding label index and low expression in optical density; 3. there was no statistical significance among expressions and tumor severity according to Gleason's score; 4. no significant correlation could be set between the biomarkers themselves.

Erythrocyte ascorbic acid and plasma vitamin E status in patients with carcinoma of prostate.

Prostate cancer is the most prevalent cancer found in men above the age of fifty years and is frequently diagnosed in men between 45 and 89 years of age with a median age of 72 years. This work was undertaken to assess oxidative stress and antioxidant status in patients with carcinoma of prostate. Erythrocyte ascorbic acid and plasma vitamin E levels were estimated in patients with carcinoma of prostate and compared to controls. It was observed that there was a significant decrease in Erythrocyte ascorbic acid and plasma vitamin E levels in patients with carcinoma of prostate compared to controls. The decrease in the levels of antioxidant vitamins may be due to the increased turnover for preventing the oxidative damage in these patients.

Role of the phosphatase PP4 in the activation of JNK-1 in prostate carcinoma cell lines PC-3 and LNCaP resulting in increased AP-1 and EGR-1 activity

The specific signaling connections between the mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK-1) and phosphatases PP4 and M3/6, affecting the family of early nuclear factors, is complex and remains poorly understood. JNK-1 regulates cellular differentiation, apoptosis and stress responsiveness by up-regulating early nuclear factors such as c-Jun, a member of the activating protein (AP-1) family, and the Early Growth Factor (EGR-1). C-Jun, when phosphorylated by c-Jun N-terminal kinase (JNK-1) associates with c-Fos to form the AP-1 transcription factor that activates gene expression. We have investigated the regulation of the JNK-1 kinase by co-transfecting phosphatases PP4 and M3/6 in prostate cancer cell lines PC-3 and LNCaP, which have been previously stimulated with human EGF or cisplatin. Co-transfections of plasmids expressing the JNK-1 and the serine/threonine phosphatases PP4 resulted in a significant increase in JNK-1 activity in both PC3 and LNCaP cells. In contrast, co-transfection of JNK-1 with the dual specific phosphatase serine/threonine M3/6 showed only a marginal effect in JNK-1 activity. The phosphatase M3/6 also failed in blocking the induction of JNK-1 activity observed in presence of PP4. The higher activity of JNK-1 was associated with increased activities of the factors c-Jun/AP-1 and EGR-1. This suggests that JNK-1 activity in PC-3 and LNCaP cells requires not only active PP4 for stable maintenance but also suggests that the relative degree of phosphorylation of multiple cellular components is the determinant of JNK-1 stability.

The role of HER2/neu, BCL2, p53 genes and proliferating cell nuclear protein as molecular prognostic parameters in localized prostate carcinoma

CONTEXTO: Câncer de próstata é a neoplasia geniturinária sólida mais freqüente no homem. Alguns genes foram identificados na iniciação e progressão do carcinoma de próstata. OBJETIVO: Estudar a expressão dos oncogenes HER2/neu e BCL2, do gene supressor p53, e da taxa de proliferação tumoral em 150 espécimes de prostatectomia radical, para definir o papel prognóstico desses parâmetros no câncer de próstata localizado. TIPO DE ESTUDO: Estudo prospectivo. LOCAL: Universidade Federal de São Paulo e Hospital Sírio Libanês, São Paulo. PARTICIPANTES: Cento e cinqüenta homens foram submetidos a prostatectomia radical entre agosto 1997 e agosto 1998, por câncer de próstata localizado. VARIAVEIS ESTUDADAS: Todos os espécimes foram submetidos à avaliação da porcentagem de volume tumoral, da extensão do tumor e da escala de Gleason. Imunohistoquímica foi realizada para determinar a expressão genética dos seguintes anticorpos: anti-HER2/neu, BCL2, p53, e proteína nuclear de proliferação celular. O teste qui-quadrado foi utilizado na correlação entre a expressão genética, a atividade proliferativa e as variáveis histológicas. RESULTADOS: Trinta por cento dos casos eram p53 positivos. Houve correlação positiva entre a expressão do p53 e o estágio tumoral. A porcentagem de expressão do p53 foi de 22.9% e de 42.6% para tumores pT2 e pT3, respectivamente, (p = 0,01). As expressões de HER2/neu, BCL2 e proteína nuclear de proliferação celular foram identificadas em 66%, 23% e 43% dos pacientes, respectivamente. Não houve correlação entre esses três parâmetros e o volume tumoral, a escala de Gleason ou o estágio da neoplasia. CONCLUSAO: Um terço dos adenocarcinomas prostáticos expressam a proteína p53, e essa característica está relacionada ao estágio tumoral. HER2/neu está freqüentemente expressado nos carcinomas de próstata, mas não existe correlação com os parâmetros histológicos. BCL2 e proteína nuclear de proliferação celular raramente estão expressados, não havendo correlação destes com as variáveis de prognóstico patológicos nessa neoplasia.

Carcinoma neuroendocrino de próstata / Neuroendocrine carcinoma of the prostate

Small cell of undifferenciated tumors are present in almost all organs, and it impose the need of performing a differential diagnosis between undifferenciated tumors with residual differentiation according to the type of organ, and the carcinoma of small cells of neuroendocrine origin. The concept of neuroendocrine differentiation (NED) in the prostatic adenocarcinoma has reached considerable attention due to its prognostic and therapeutic implies. Here it is presented a new neuroendocrine prostatic carcinoma case taking care of its hystopathologic diagnosis and evolution.

Los tumores indiferenciados de células pequeñas pueden ser encontrados prácticamente en todos los órganos, imponiendo la necesidad de realizar el diagnóstico diferencial entre tumores indiferenciados con diferenciación residual según el tipo de órgano y el carcinoma de células pequeñas de origen neuroendocrino. El concepto de diferenciación neuroendocrina (DNE) en el adenocarcinoma de próstata ha recibido recientemente considerable atención debido a sus implicancias pronosticas y terapéuticas. Se presenta un nuevo caso de carcinoma neuroendocrino de próstata con consideraciones sobre su diagnóstico histopatológico y su evolución.