Zielsetzung: Die diffusionsgewichtete Bildgebung ist wesentlicher Bestandteil der Magnetresonanz-tomographie des Prostatakarzinoms (PCa). Aus entsprechenden Rohdaten, aufgenommen bei verschie-denen b-Werten (Diffusionswichtungsfaktoren), kann der Diffusionskoeffizient (apparent diffusion coefficient - ADC) abgeschätzt werden, der ein sensitiver Indikator für maligne Veränderungen der Gewebearchitektur ist. Die absoluten ADC-Werte sind allerdings stark von der Wahl der zugrundeliegenden b-Werte abhängig und darüber hinaus gibt es Hinweise, dass die Wahl der b-Werte einen signifikanten Einfluss auf die visuelle Analyse, insbesondere auf die Abgrenzbarkeit der Läsion von der Umgebung und auf den Kontrast hat. Es wurde daher untersucht, inwieweit die Wahl der b-Werte den diagnostischen Wert des ADC im Hinblick auf die Detektion und Beurteilung des PCa hat. Methodik: 41 konsekutive Patienten mit gesichertem PCa erhielten eine multiparametrische, endorektale MR-Bildgebung bei 3 Tesla. Die ADC-Karten wurden retrospektiv auf Basis vier verschiedener Kombinationen von b-Werten (0-800 s/mm2) berechnet. Drei Untersucher bestimmten die „führende“ Läsion und beurteilten dann den diagnostischen Wert der jeweiligen ADC-Karten (Visual Score - VS) mit sehr gut (2), befriedigend (1) oder schlecht (0). Für die quantitative Auswertung wurden der mittlere ADC für gesundes und für Tumorgewebe bestimmt. Unterschiede in Abhängigkeit von den gewählten b-Werten wurden mittels statistischer Tests (einseitige ANOVA, Faktor Methode, Signifikanzniveau 5 %) ausgewertet. Ergebnisse: 85 % der Tumoren wurden von den Auswertern richtig erkannt. Die Wahl der b-Werte hatte hochgradig signifikanten (P<0,001) Einfluss auf die absoluten ADC-Werte in gesundem und verändertem Gewebe. ADC-Karten auf Basis von b=[50, 800] und [0, 800] wurden am besten (VS=1,6±0,3) und zweitbesten (VS=1,1±0,3; P<0,001) bewertet. Insbesondere für niedrig-gradige Karzinome (Gleason Score ≤ 6, 13/41 Patienten), wurde nur die Kombination [50, 800] besser als befriedigend (VS=1,4±0,3) bewertet. Der mittlere Tumor-ADC zeigte eine moderate aber signifikant negative Korrelation (Spearman ρ: -0,38 bis -0,46; P<0,05) mit dem Gleason Score. Schlussfolgerung: Absolute ADC-Werte sind stark von der Wahl der zugrundeliegenden b-Werte abhängig und eignen sich daher nicht zur allgemeingültigen Charakterisierung von Prostatakarzinomen. Ein minimaler b-Wert > 0 s/mm2 wird für die Berechnung der ADC-Karten im Hinblick auf eine nachweislich verbesserte visuelle Auswertbarkeit empfohlen.

Zielsetzung: Die diffusionsgewichtete Bildgebung ist wesentlicher Bestandteil der Magnetresonanz-tomographie des Prostatakarzinoms (PCa). Aus entsprechenden Rohdaten, aufgenommen bei verschie-denen b-Werten (Diffusionswichtungsfaktoren), kann der Diffusionskoeffizient (apparent diffusion coefficient - ADC) abgeschätzt werden, der ein sensitiver Indikator für maligne Veränderungen der Gewebearchitektur ist. Die absoluten ADC-Werte sind allerdings stark von der Wahl der zugrundeliegenden b-Werte abhängig und darüber hinaus gibt es Hinweise, dass die Wahl der b-Werte einen signifikanten Einfluss auf die visuelle Analyse, insbesondere auf die Abgrenzbarkeit der Läsion von der Umgebung und auf den Kontrast hat. Es wurde daher untersucht, inwieweit die Wahl der b-Werte den diagnostischen Wert des ADC im Hinblick auf die Detektion und Beurteilung des PCa hat. Methodik: 41 konsekutive Patienten mit gesichertem PCa erhielten eine multiparametrische, endorektale MR-Bildgebung bei 3 Tesla. Die ADC-Karten wurden retrospektiv auf Basis vier verschiedener Kombinationen von b-Werten (0-800 s/mm2) berechnet. Drei Untersucher bestimmten die „führende“ Läsion und beurteilten dann den diagnostischen Wert der jeweiligen ADC-Karten (Visual Score - VS) mit sehr gut (2), befriedigend (1) oder schlecht (0). Für die quantitative Auswertung wurden der mittlere ADC für gesundes und für Tumorgewebe bestimmt. Unterschiede in Abhängigkeit von den gewählten b-Werten wurden mittels statistischer Tests (einseitige ANOVA, Faktor Methode, Signifikanzniveau 5 %) ausgewertet. Ergebnisse: 85 % der Tumoren wurden von den Auswertern richtig erkannt. Die Wahl der b-Werte hatte hochgradig signifikanten (P<0,001) Einfluss auf die absoluten ADC-Werte in gesundem und verändertem Gewebe. ADC-Karten auf Basis von b=[50, 800] und [0, 800] wurden am besten (VS=1,6±0,3) und zweitbesten (VS=1,1±0,3; P<0,001) bewertet. Insbesondere für niedrig-gradige Karzinome (Gleason Score ≤ 6, 13/41 Patienten), wurde nur die Kombination [50, 800] besser als befriedigend (VS=1,4±0,3) bewertet. Der mittlere Tumor-ADC zeigte eine moderate aber signifikant negative Korrelation (Spearman ρ: -0,38 bis -0,46; P<0,05) mit dem Gleason Score. Schlussfolgerung: Absolute ADC-Werte sind stark von der Wahl der zugrundeliegenden b-Werte abhängig und eignen sich daher nicht zur allgemeingültigen Charakterisierung von Prostatakarzinomen. Ein minimaler b-Wert > 0 s/mm2 wird für die Berechnung der ADC-Karten im Hinblick auf eine nachweislich verbesserte visuelle Auswertbarkeit empfohlen.

O câncer de próstata (CaP) é o tumor maligno mais frequente e uma das principais causas de morte por câncer na população masculina no mundo e no Brasil. Três fatores são de fundamental importância no prognóstico da doença: o estadiamento, o grau histológico (avaliado pelo escore de Gleason) e o antígeno prostático específico (Prostate Specific Antigen - PSA). Há fatores adicionais descritos que podem influenciar na evolução do câncer, como invasão perineural, invasão angiolinfática, acometimento da cápsula, lateralidade do tumor, estágio tumoral e invasão de linfonodos. Embora a associação entre mutações do BRCA2 e o risco de câncer de próstata esteja bem documentado, pouco se sabe sobre o papel do BRCA2 na progressão do câncer de próstata após o diagnóstico inicial. O presente trabalho se propõe a melhor elucidar o papel da proteína BRCA2 nos carcinomas prostáticos comparando os resultados da expressão proteica de BRCA2 com dados clinicopatológicos de pacientes acometidos por Câncer de Próstata, além de avaliar a expressão de BRCA2 com escore de Gleason >=7 após a prostatectomia, tanto na classificação de Gleason segundo Epstein 2005, quanto na classificação do grau de Gleason definida em 2014 com suas respectivas biópsias por agulha. Dos arquivos do Serviço de Patologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, foram selecionados 125 blocos de parafina com amostras de câncer de próstata diagnosticados entre 2005 e 2010. As lâminas coradas com hematoxilina e eosina (H&E) foram utilizadas para a construção de microarranjos teciduais (TMAs). Nesses TMAs foi realizado estudo imunohistoquímico para BRCA2. A proteína BRCA2 com ponto de corte de 15% (classificação antiga) foi superexpressa em 118 casos (94,4%), enquanto a expressão de BRCA2 com cut-off de 56% (classificação nova) foi expressa em 63 (51,2%) de 125 casos. A superexpressão de BRCA2 associada a classificação antiga de Gleason correlacionou-se com bilateralidade do tumor e com estágio tumoral, em contrapartida a expressão de BRCA2 associada a atual classificação se correlacionou apenas com lesão intraepitelial prostática (PIN). Nossos resultados indicam que a expressão de BRCA2 pode ser um biomarcador importante de progressão tumoral nos carcinomas de próstata. / Prostate cancer (PCa) is the most common malignancy and a major cause of cancer death in male population in the world and in Brazil. Three factors are of fundamental importance in the prognosis of the disease: the staging, histological grade (measured by Gleason score) and the Prostate Specific Antigen (PSA). There are additional factors described that may influence the development of cancer, such as perineural invasion, angiolymphatic invasion, capsule involvement, tumor laterality, tumor stage and lymph node invasion. Although the association between mutations in Breast Cancer Gene 2 (BRCA2) and the risk of prostate cancer is well documented, little is known about the role of BRCA2 in the progression of prostate cancer after initial diagnosis. This study aims to elucidate the role of BRCA2 protein in prostate carcinomas comparing the results of the BRCA2 protein expression with clinicopathological data of patients with prostate cancer. For that reason, we evaluated the expression of BRCA2 with Gleason score >=7 after prostatectomy, both in the second Epstein 2005 Gleason score, and in the classification of Gleason grade set in 2014 with their respective needle biopsies. 125 paraffin blocks with prostate cancer samples diagnosed between 2005 and 2010 were selected from the archives of Hospital Pathology Service of the Ribeirao Preto Medical School, University of Sao Paulo. The slides stained with hematoxylin and eosin (H&E) were used for the construction of the tissue microarrays (TMAs). These TMAs was performed immunohistochemical study for BRCA2. The BRCA2 protein with a cut-off point of 15% (old classification) was overexpressed in 118 cases (94.4%), while the expression of BRCA2 to cut off 56% (new classification) was expressed in 63 (51.2%) of 125 cases. The BRCA2 associated overexpression of the old classification of Gleason presented correlation with tumor bilateralism and tumor stage, however BRCA2 expression associated with the current classification was correlated only with Prostatic Intraepithelial Lesion (PIN). Our results indicate that BRCA2 expression can be an important marker of tumor progression in prostate carcinomas.

O câncer de próstata (CaP) é o tumor maligno mais frequente e uma das principais causas de morte por câncer na população masculina no mundo e no Brasil. Três fatores são de fundamental importância no prognóstico da doença: o estadiamento, o grau histológico (avaliado pelo escore de Gleason) e o antígeno prostático específico (Prostate Specific Antigen - PSA). Há fatores adicionais descritos que podem influenciar na evolução do câncer, como invasão perineural, invasão angiolinfática, acometimento da cápsula, lateralidade do tumor, estágio tumoral e invasão de linfonodos. Embora a associação entre mutações do BRCA2 e o risco de câncer de próstata esteja bem documentado, pouco se sabe sobre o papel do BRCA2 na progressão do câncer de próstata após o diagnóstico inicial. O presente trabalho se propõe a melhor elucidar o papel da proteína BRCA2 nos carcinomas prostáticos comparando os resultados da expressão proteica de BRCA2 com dados clinicopatológicos de pacientes acometidos por Câncer de Próstata, além de avaliar a expressão de BRCA2 com escore de Gleason >=7 após a prostatectomia, tanto na classificação de Gleason segundo Epstein 2005, quanto na classificação do grau de Gleason definida em 2014 com suas respectivas biópsias por agulha. Dos arquivos do Serviço de Patologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, foram selecionados 125 blocos de parafina com amostras de câncer de próstata diagnosticados entre 2005 e 2010. As lâminas coradas com hematoxilina e eosina (H&E) foram utilizadas para a construção de microarranjos teciduais (TMAs). Nesses TMAs foi realizado estudo imunohistoquímico para BRCA2. A proteína BRCA2 com ponto de corte de 15% (classificação antiga) foi superexpressa em 118 casos (94,4%), enquanto a expressão de BRCA2 com cut-off de 56% (classificação nova) foi expressa em 63 (51,2%) de 125 casos. A superexpressão de BRCA2 associada a classificação antiga de Gleason correlacionou-se com bilateralidade do tumor e com estágio tumoral, em contrapartida a expressão de BRCA2 associada a atual classificação se correlacionou apenas com lesão intraepitelial prostática (PIN). Nossos resultados indicam que a expressão de BRCA2 pode ser um biomarcador importante de progressão tumoral nos carcinomas de próstata. / Prostate cancer (PCa) is the most common malignancy and a major cause of cancer death in male population in the world and in Brazil. Three factors are of fundamental importance in the prognosis of the disease: the staging, histological grade (measured by Gleason score) and the Prostate Specific Antigen (PSA). There are additional factors described that may influence the development of cancer, such as perineural invasion, angiolymphatic invasion, capsule involvement, tumor laterality, tumor stage and lymph node invasion. Although the association between mutations in Breast Cancer Gene 2 (BRCA2) and the risk of prostate cancer is well documented, little is known about the role of BRCA2 in the progression of prostate cancer after initial diagnosis. This study aims to elucidate the role of BRCA2 protein in prostate carcinomas comparing the results of the BRCA2 protein expression with clinicopathological data of patients with prostate cancer. For that reason, we evaluated the expression of BRCA2 with Gleason score >=7 after prostatectomy, both in the second Epstein 2005 Gleason score, and in the classification of Gleason grade set in 2014 with their respective needle biopsies. 125 paraffin blocks with prostate cancer samples diagnosed between 2005 and 2010 were selected from the archives of Hospital Pathology Service of the Ribeirao Preto Medical School, University of Sao Paulo. The slides stained with hematoxylin and eosin (H&E) were used for the construction of the tissue microarrays (TMAs). These TMAs was performed immunohistochemical study for BRCA2. The BRCA2 protein with a cut-off point of 15% (old classification) was overexpressed in 118 cases (94.4%), while the expression of BRCA2 to cut off 56% (new classification) was expressed in 63 (51.2%) of 125 cases. The BRCA2 associated overexpression of the old classification of Gleason presented correlation with tumor bilateralism and tumor stage, however BRCA2 expression associated with the current classification was correlated only with Prostatic Intraepithelial Lesion (PIN). Our results indicate that BRCA2 expression can be an important marker of tumor progression in prostate carcinomas.

PURPOSE: To determine the accuracy of prostate biopsy Gleason score (GS) compared to prostatectomy GS. To determine whether a biopsy is a satisfactory diagnostic procedure to offer active surveillance for patients with low-grade prostate cancer. METHODS: This study was conducted in Tuft Medical Center as retrospective cohort study over the period from 2007-2010. The study included 83 patients for whom biopsy and prostatectomy GS were available. MEASUREMENTS: Gleason scores of 6, 7, and 8-10 were assigned to low, moderate, and high-grades, respectively. The kappa statistic was calculated to assess the degree of agreement between biopsy and prostatectomy. The ROC curve was used to evaluate the sensitivity and specificity of prostate biopsy for different Gleason grades. Also, compared whether the use of specific criteria for active surveillance (Johns Hopkins and UCSF) may decrease the level of up-grading in patient with low-grade prostate cancer using Chi-square test. RESULTS: The distribution of low, moderate, and high-grade cancer in biopsy (52%, 32%, 16%) and prostatectomy specimen (33%, 55%, 12%) showed fair agreement with weighted kappa 0.35. The prostate biopsy accurately predicted GS in 46%, up-graded in 38%, and down-graded in 16%. The patients with low-grade cancer and potentially eligible for active surveillance showed up-grading in 50% of cases. This up-grading reduced to 40% with the use of Johns Hopkins criteria and to 41% with the use of UCSF criteria. CONCLUSIONS: The accuracy of biopsy GS in predicting prostatectomy GS is severely limited and therefore biopsy is not enough diagnostic procedure to offer active surveillance.

PURPOSE: This study was undertaken to compare HALO™ software image analysis measurements of cellularity with visual estimations from the pathologist and to outline a protocol for future experimental determinations of cellularity using HALO™. Secondly, this study investigated the clinically challenging prostate cancers of Gleason score 7 by analyzing a large database of radical prostatectomy (RP) specimens with regard to their Gleason grade composition and percentage tumor volume composition. The importance of these values of tumor cellularity, prostate volume, and tumor volume data were discussed in terms of future diagnostic endeavors. Finally, this study provided a brief background on prostate cancer, prostate cancer epidemiology, digital pathology, and the limitations and difficulties in the technological transition to digital pathology. All work for this study was done at Dana-Farber Cancer Institute (Boston, MA). METHODS: In the first part of this study, histological slides were acquired by radical prostatectomy (RP) and contained 12 tumor foci of varying degrees and sizes. These slides were scanned and imported into the HALO™ image analysis software. The tumor foci, previously demarcated by a pathologist, were annotated by hand in HALO™. An algorithm for image analysis was created by training classifiers to recognize and differentiate between epithelial tissue, stromal tissue, glass, and other. This process was accomplished by classifying 62 regions which were tested for accuracy before becoming the components of an algorithm to analyze the entire annotation layer. Each tumor focus was analyzed individually, and the results were exported into Microsoft® Excel from which relevant data were extracted. Cellularity was calculated by the percentage of tumor area that the algorithm characterized as epithelial. Cellularity values derived from HALO™ measurements for each tumor focus were compared with the visual estimations of cellularity provided by the pathologist using Pearson's correlation analysis. In the second part of this study, a database of 1386 slides containing tumors with Gleason scores between 6 and 9 was compiled from 140 RP cases. The average percentages of Gleason grades 3, 4, and 5 in each case were determined. The percentage of each slide that was occupied by the tumor was also averaged for each case, yielding an average percentage of tumor volume for each case. The average Gleason grade 3, 4, or 5 percentage for each case was plotted against the associated average tumor volume percentage of that case. The cases of Gleason score 7 (3+4, 4+3) were then isolated and plotted in a similar manner. Pearson’s correlation analysis was used to determine the degree of linear correlation between the two variables in each plot. Results: In the first part of this study, a statistically significant positive correlation between the cellularity estimations of the pathologist and the HALO™ cellularity measurements was found (r = 0.92, p < 0.01, n =12). In the second part of this study, there was a statistically significant negative correlation between average Gleason grade 3 percentage per case and average tumor volume percentage per case (r = -0.55, p <0.001, n = 140). There was also a statistically significant positive correlation between average Gleason grade 4 percentage per case and average tumor volume percentage per case (r = 0.55, p <0.001, n = 140). After slides containing Gleason score 6 (3+3) tumor were removed from the data, a statistically significant negative correlation remained between average Gleason grade 3 percentage per case and average tumor volume percentage per case (r = -0.51, p <0.001, n = 78), and a statistically significant positive correlation remained between average Gleason grade 4 percentage per case and average tumor volume percentage per case (r = 0.5, p <0.001, n = 101). A statistically significant relationship between average Gleason grade 5 percentage and average tumor volume percentage was not found (r = 0.32, p = 0.14, n = 23). CONCLUSIONS: In the first part of this study, the strong positive correlation between HALO™ cellularity values and visual estimations by the pathologist suggests that image analysis may be an effective tool for determining cellularity in digital histological images. More research using larger sample sizes is recommended to further validate the correlation between algorithm-derived cellularity from HALO™ and visual estimation by the pathologist. In the second part of this study, it appears that the volume of prostate tumors of Gleason score 7 may have prognostic power, considering that an increased percentage composition of Gleason grade 4 correlated with larger tumor volumes. Because this result may have significant clinical implications, further research specifically on tumors of Gleason score 7 is suggested to verify this relationship.

O objetivo deste trabalho foi avaliar se a expressão do colágeno tipo I, III e metaloproteinase podem estar relacionadas com o grau de Gleason, estadio patológico e PSA pré-operatório, e se isto poderia servir como prognóstico de doença. O grupo de estudo incluiu espécimes de prostatectomia radical de 33 pacientes com adenocarcinoma submetidos à cirurgia no período de 2001 a 2009. Os pacientes foram divididos em 3 grupos: grau de Gleason = 6 (13 pacientes), escore de Gleason = 7 (10 pacientes), escore de Gleason &#8805; 8 (10 pacientes). O tecido prostático benigno adjacente à area de câncer nos graus de Gleason foi utilizado como grupo controle. As áreas de adenocarcinoma e de tecido benigno foram selecionados sob análise microscópica e processados para colágeno I e III sob análise do gene por PCR em Tempo Real. Dez seções desparafinadas de cada grupo foram utilizados para avaliar o colágeno I, III e a imunoexpressão de metaloproteinase. Os resultados foram relacionados com o grau de Gleason, PSA pré-operatório e estadio patológico. Apesar da diferença significativa na expressão gênica de ambos colágeno I e III entre as áreas de tecido prostático benigno e tumor nas amostras de próstata Gleason = 6 (colágeno I = 0,4 0,2 vs 5 2,4, p<0,05; colágeno III = 0,2 0,06 vs 0,7 0,1, p<0,05) e grau de Gleason &#8805; 8 (I = 8 3,4 vs 1,4 0,8, p<0,05; colágeno III = 1,8 0,5 vs 0,6 0,1, p<0,05), não houve correlação com grau de Gleason, PSA pré-operatório ou estadio patológico. Houve uma correlação positiva entre a expressão de metaloproteinases e grau de Gleason (r2 = 0,47). Concluindo, tem-se que a correlação positiva entre a expressão de metaloproteinases e o grau de Gleason sugere que a metaloproteinase pode ser um fator promissor para melhorar o grau de Gleason. Sua expressão e regulação não parecem estar relacionados com a degradação do colágeno. Não há correlação entre expressão de colágeno e grau de Gleason, nem a nível gênico nem protéico. / Purpose: The aim of this paper was to evaluate if the expression of metalloproteinase, collagen I and III could be related with Gleason score, preoperative PSA and pathological stage. Materials and Methods: Our study group included radical prostatectomy specimens of 33 patients with prostatic adenocarcinoma who underwent surgery in the period from 2001 to 2009. Patients were divided into 3 groups: Gleason score=6 (13 patients), Gleason score=7 (10 patients), Gleason score &#8805;8 (10 patients). Benign prostatic tissues adjacent to the cancer area in the different Gleason grades were used as a control group. The adenocarcinoma and benign areas were selected from the tissues under microscope analysis and further processed for collagen I and III gene analysis by Real Time PCR. Ten deparaffined sections of each group were used to evaluate collagen I, III and metalloproteinase immunoexpression. The results were related with Gleason score, preoperative PSA and pathological stage. Results: Despite the significant difference in both collagen I and III gene expression between benign and tumor areas in the prostate samples from Gleason score=6 (collagen I=0.40.2 vs 52.4,p<0.05; collagen III= 0.20.06 vs 0.70.1,p<0.05) and Gleason score&#8805;8 (collagen I= 83.4 vs 1.40.8,p<0.05; collagen III= 1.80.5 vs 0.60.1,p<0.05), there was no correlation with Gleason score, preoperative PSA or pathological stage. There was a positive correlation between metalloproteinase expression and Gleason score (r2=0.47). Conclusions: The positive correlation between metalloproteinase expression and Gleason score suggests that metalloproteinase could be a promissing factor to improve Gleason score. Its expression and regulation do not seem to be related with collagen degradation.

O objetivo deste trabalho foi avaliar se a expressão do colágeno tipo I, III e metaloproteinase podem estar relacionadas com o grau de Gleason, estadio patológico e PSA pré-operatório, e se isto poderia servir como prognóstico de doença. O grupo de estudo incluiu espécimes de prostatectomia radical de 33 pacientes com adenocarcinoma submetidos à cirurgia no período de 2001 a 2009. Os pacientes foram divididos em 3 grupos: grau de Gleason = 6 (13 pacientes), escore de Gleason = 7 (10 pacientes), escore de Gleason &#8805; 8 (10 pacientes). O tecido prostático benigno adjacente à area de câncer nos graus de Gleason foi utilizado como grupo controle. As áreas de adenocarcinoma e de tecido benigno foram selecionados sob análise microscópica e processados para colágeno I e III sob análise do gene por PCR em Tempo Real. Dez seções desparafinadas de cada grupo foram utilizados para avaliar o colágeno I, III e a imunoexpressão de metaloproteinase. Os resultados foram relacionados com o grau de Gleason, PSA pré-operatório e estadio patológico. Apesar da diferença significativa na expressão gênica de ambos colágeno I e III entre as áreas de tecido prostático benigno e tumor nas amostras de próstata Gleason = 6 (colágeno I = 0,4 0,2 vs 5 2,4, p<0,05; colágeno III = 0,2 0,06 vs 0,7 0,1, p<0,05) e grau de Gleason &#8805; 8 (I = 8 3,4 vs 1,4 0,8, p<0,05; colágeno III = 1,8 0,5 vs 0,6 0,1, p<0,05), não houve correlação com grau de Gleason, PSA pré-operatório ou estadio patológico. Houve uma correlação positiva entre a expressão de metaloproteinases e grau de Gleason (r2 = 0,47). Concluindo, tem-se que a correlação positiva entre a expressão de metaloproteinases e o grau de Gleason sugere que a metaloproteinase pode ser um fator promissor para melhorar o grau de Gleason. Sua expressão e regulação não parecem estar relacionados com a degradação do colágeno. Não há correlação entre expressão de colágeno e grau de Gleason, nem a nível gênico nem protéico. / Purpose: The aim of this paper was to evaluate if the expression of metalloproteinase, collagen I and III could be related with Gleason score, preoperative PSA and pathological stage. Materials and Methods: Our study group included radical prostatectomy specimens of 33 patients with prostatic adenocarcinoma who underwent surgery in the period from 2001 to 2009. Patients were divided into 3 groups: Gleason score=6 (13 patients), Gleason score=7 (10 patients), Gleason score &#8805;8 (10 patients). Benign prostatic tissues adjacent to the cancer area in the different Gleason grades were used as a control group. The adenocarcinoma and benign areas were selected from the tissues under microscope analysis and further processed for collagen I and III gene analysis by Real Time PCR. Ten deparaffined sections of each group were used to evaluate collagen I, III and metalloproteinase immunoexpression. The results were related with Gleason score, preoperative PSA and pathological stage. Results: Despite the significant difference in both collagen I and III gene expression between benign and tumor areas in the prostate samples from Gleason score=6 (collagen I=0.40.2 vs 52.4,p<0.05; collagen III= 0.20.06 vs 0.70.1,p<0.05) and Gleason score&#8805;8 (collagen I= 83.4 vs 1.40.8,p<0.05; collagen III= 1.80.5 vs 0.60.1,p<0.05), there was no correlation with Gleason score, preoperative PSA or pathological stage. There was a positive correlation between metalloproteinase expression and Gleason score (r2=0.47). Conclusions: The positive correlation between metalloproteinase expression and Gleason score suggests that metalloproteinase could be a promissing factor to improve Gleason score. Its expression and regulation do not seem to be related with collagen degradation.

Purpose: To evaluate the validity of the Gleason score after neoadjuvant hormonal treatment as predictor of diseasespecific mortality after radical prostatectomy. Patients and Methods: A total of 2,880 patients with a complete data set and a mean follow-up of 10.3 years were studied; 425 of them (15%) had a history of hormonal treatment prior to surgery. The cumulative incidence of deaths from prostate cancer was determined by univariate and multivariate competing risk analysis. Cox proportional hazard models for competing risks were used to study combined effects of the variables on prostate cancer-specific mortality. Results: A higher portion of specimens with a history of neoadjuvant hormonal treatment were assigned Gleason scores of 8–10 (28 vs. 17%, p < 0.0001). The mortality curves in the Gleason score strata <8 vs. 8–10 were at large congruent in patients with and without neoadjuvant hormonal treatment. In patients with neoadjuvant hormonal treatment, a Gleason score of 8–10 was an independent predictor of prostate cancer-specific mortality; the hazard ratio was, however, somewhat lower than in patients without neoadjuvant hormonal treatment. Conclusion: This study suggests that the prognostic value of the post-radical prostatectomy Gleason score is not meaningfully jeopardized by heterogeneous neoadjuvant hormonal treatment in a routine clinical setting.

Der Gleason-Score ist ein wichtiges Kriterium für die prognostische Einteilung des Prostatakarzinoms und sollte auch am positiven Resektionsrand bestimmt werden. Es wurden 1 836 Prostatakarzinomfälle aus den Jahren 2006-2010 analysiert. Dabei wurden Anzahl sowie Lokalisation der R1-Resektionen; der Gleason-Score und die Länge (mm) des positiven Resektionsrand bestimmt. Danach wurden Unterschiede zwischen R0- und R1-resezierten Patienten; Unterschiede innerhalb der R1-Kohorte und die Länge des positiven Resektionsrands ausgewertet. Es erfolgte eine statistisch-explorative Analyse der Überlebenszeit der R1-Kohorte und der Einfluss der klinisch-pathologischen Variablen (Alter, PSA, pT-, pN-Kategorie, EPE, Gleason-Score im Tumor, Gleason-Score am Resektionsrand, Länge des Resektionsrand, Operationsmodus) auf die Prognose des Prostatakarzinoms. Alle Einteilungen wurden anhand der TNM-Klassifikation 7. Auflage, (UICC), Gleason-Grading-System Revision 2015 (ISUP) und dem prognostischen Gruppierungssystem der ISUP 2015 vorgenommen. Nach radikaler Prostatektomie zeigten 242 (13,2 %) Patienten eine R1-Resektion und 166 (9 %) ein biochemisches Rezidiv. Es zeigte sich, dass in der R1-Kohorte gegenüber der R0-Kohorte mehr pT3-/pT3b-/pT4-Kategorien, mehr positive Lymphknoten, Infiltrationen der Perineuralscheiden und Venen, EPE und Samenblaseninfiltrationen auftraten ( p <0,001). In der R0-Kohorte häuften sich die Gleason-Scores 6 und 7a (25,4 % | 47,5 %), in der R1-Kohorte dagegen die Werte 8 und 9-10 (28,5 % | 17,8 %). Von 242 positiven Resektionsrändern unterschieden sich 147 (60,74 %) in ihrem Gleason-Score vom Gleason-Score des Tumors, 103 (42,56 %) hatten einen niedrigeren und 44 (18,18 %) einen höheren Gleason-Score am Resektionsrand. Die Analyse der R1-Kohorte mittels der ISUP-Grade zeigte, dass in Präparaten mit Gleason-Score von 6 und 7a mehr pT2c- und pT3a-Kategorien vorhanden waren, dagegen in solchen mit Gleason-Score 7b, 8 und 9-10 ein Anstieg von pT3b- und pT4-Kategorien zu verzeichnen war. Mit steigendem ISUP-Grad kam es zum Anstieg der pN-Kategorie, der EPE und der Infiltrationen der Samenblase sowie der Anzahl und medianen Länge der positiven Resektionsränder. Nach Kaplan-Meier wurde der Einfluss der o.g. Variablen auf die Überlebenszeit bis zum biochemischen Rezidiv überprüft. Die roboterassistierten Prostatektomien zeigten mit (82 Mon. | CI 70-96) im Vergleich mit den retropubischen (72 Mon. | CI 68–76) und laparoskopischen (53 Mon. | CI 39–67) die höchste Überlebensrate. Nach 85 Mon. hatten 70 % der R1-Resezierten ein Rezidiv vs. 30 % R0-Resezierter. Überraschend ergab sich innerhalb der R1-Kohorte eine prognostisch „gute“ Gruppe aus Gleason-Score 6 und 7a mit Überlebenszeiten von (72 Mon. | (CI 50–95) || 49 Mon.|(CI 30–69)). Die prognostisch „schlechte“ Gruppe bildeten Gleason-Score 7b, 8, 9-10 (27 Mon. | (CI 16–38), 25 Mon. | (CI 14–36) & 24 Mon. | (CI 11–36)). Patienten mit Gleason-Score ≤6 und 7a am Resektionsrand zeigten (53 bzw. 51 Mon. | CI 50–95) im Vergleich zu Gleason-Score 7b, 8 und 9-10 (25; 24 bzw. 26 Mon.|CI 15–36) rezidivfreies Überleben. Patienten mit Gleason-Score 6 zeigten bei R0- (82 Mon. | CI 78–98) und R1-Resektion (72 Mon | CI 51–94) nur einen geringen Unterschied. Positive Resektionsränder ≤3mm vs. ≥3mm zeigten wie nur ein positiver Resektionsrand vs. multiple positive Resektionsränder ein längeres Überleben. Mittels Cox-Regression wurden die o.g. Variablen auf ihr Risiko für die Entstehung eines biochemischen Rezidivs überprüft. In der univariaten Analyse ergaben sich hohe Risiken für die Gleason-Scores 7b, 8 & 9-10 am positiven Resektionsrand (HR 2,5 bis HR 2,3) und für multiple positive Resektionsränder (HR 2,1). Die multivariate Cox-Regression mit Basis pT-Kategorie ergab eine Steigerung des Risikos für ein Rezidiv durch die Gleason-Scores am Resektionsrand 7b und 8 (HR 1,8) sowie für den positiven Resektionsrand ≥3mm (HR 1,4). Wurde der Gleason-Score des Tumors als Basis genutzt, so erhöhte sich das Risiko für ein Rezidiv durch den Gleason-Score des Resektionsrands 9-10 (HR 1,8), den positiven Resektionsrand ≥3mm (HR 1,4) und multiple positive Resektionsränder (HR 1,4). Auf Basis dieser Ergebnisse ist die Bestimmung des Gleason-Scores am Resektionsrand sowie der Länge und Anzahl der positiven Resektionsränder nach R1-Resektionen erforderlich, um eine bessere Risikostratifizierung durchführen und so die angemessene Therapie auswählen zu können.:Inhaltsverzeichnis Abkürzungsverzeichnis Tabellenverzeichnis Abbildungsverzeichnis 1. Einführung 1.1 Klassifikation 1.1.1 TNM-Klassifikation 1.1.2 Gleason-Score 1.2 Forschungsstand zu positiven Resektionsrändern 1.2.1 Forschungsstand zum Gleason-Score am Resektionsrand 1.2.2 Forschungsstand zur Länge des positiven Resektionsrand 2. Ziele der Arbeit 3. Materialien und Methoden 3.1 Studienpopulation 3.2 Vorgehen der Erhebung 3.2.1 Bestimmung des Gleason-Scores am Resektionsrand 3.2.2 Bestimmung der Länge des positiven Resektionsrands 3.3 Pathologische Klassifikationen 3.4 Geräte 3.5 Statistische Methoden 4. Ergebnisse 4.1 Analyse der klinisch-pathologischen Kriterien für Grundgesamtheit, R1- und R0-Kohorte 4.1.1 Subgruppenanalyse der R1-Kohorte nach ISUP-Graden 4.2 Korrelationsanalyse von Gleason-Score und Länge des positiven Resektionsrandes 4.3 Überlebenszeitanalyse der Grundgesamtheit 4.3.1 Überlebenszeitanalyse der R1-Kohorte unter Gruppierung klinisch-pathologischer Variable 4.4 Hazard Ratios der klinisch-pathologischen Variablen 5. Diskussion 5.1 Limitationen 6. Zusammenfassung 7. Literaturverzeichnis Anhang Lebenslauf Danksagung Eigenständigkeitserklärung