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Valor preditivo de marcadores de transição epitelial - mesenquimatosa, PTEN, ERG, Ki-67 e de estudo mutacional, na recorrência bioquímica de carcinoma da próstata tratado com cirurgia
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Valor Preditivo de Marcadores de Transição Epitelial-‐Mesenquimatosa, PTEN, ERG, Ki67 e de Estudo Genético na Recorrência Bioquímica de Carcinoma da Próstata tratado com cirurgia
Introdução: O carcinoma da próstata apresenta uma elevada incidência e prevalência. A maioria dos carcinomas da próstata localizados são curáveis, com as opções terapêuticas disponíveis. Contudo, a recorrência da doença está associada a morbilidade, a mortalidade e a custos elevados. Como tal, é importante otimizar o tratamento da doença localizada. Uma das possibilidades para o fazer, passa por uma melhoria do nosso conhecimento, acerca dos factores preditivos. Um reconhecimento precoce de uma maior probabilidade de recorrência poderia levar a uma otimização da abordagem terapêutica dos tumores primários, nomeadamente através de estratégias que incluam intensificação terapêutica.
Material e Métodos: Numa amostra populacional constituída por doentes, com carcinoma da próstata localizado, e tratados com prostatectomia radical de intuito curativo, avaliámos o valor preditivo de factores clínicos, anatomopatológicos, imunohistoquímicos e genéticos. Utilizámos como “endpoint” a recorrência bioquímica (RBQ).
Resultados: Em 147 doentes, e após um seguimento, cuja mediana foi de 20 meses (4-‐55 meses), ocorreu RBQ em 15,6% dos casos. Na nossa amostra, o PSA pré-‐ operatório (p=0,02); o tipo de cirurgia (p=0,01); o score de Gleason da biópsia (p=0,004) e da lesão índice (P<0,001); a classificação de Epstein da biópsia (p=0,005), da peça (p=0,006), e da lesão índice (p<0,001); o número de fragmentos de biópsia envolvidos por tumor (p=0,05), a extensão do envolvimento tumoral nos fragmentos de biópsia, em milímetros (p=0,01) e percentualmente (p=0,02); a existência de áreas de diferenciação intraductal (p=0,003); a presença de padrão de terciário (p<0,001); a dimensão linear da lesão índice (p=0,005); a existência de margem cirúrgica positiva (p=0,05); a existência de extensão extraprostática (p=0,02); a invasão vascular (p=0,002); a invasão das vesículas seminais (p=0,01); o número de gânglios isolados em doentes submetidos a linfadenectomia (p=0,01); o estádio patológico referente ao tumor primário (p=0,02) e a pErda de expressão da caderina E (p<0,001), mostraram significância estatística relativamente à ocorrência de recorrência bioquímica. Por análise multivariável, apenas a existência de áreas de diferenciação intraductal (p=0,01), a classificação de Epstein da lesão índice (p<0,001), a invasão vascular (p=0,02) e o número de gânglios isolados em doentes submetidos a linfadenectomia (p=0,05), mantiveram a significância estatística, após ajuste para as outras variáveis. Os restantes biomarcadores associados à transição epitelial-‐mesenquimatosa (caderina N e vimentina), o PTEN, o Ki-‐67 e o ERG, na nossa amostra, e por análise univariável, não estão associados à ocorrência de RBQ. A expressão de SChLAP1, quer em tecido tumoral, quer em tecido não tumoral, também não está associado à ocorrência de RBQ.
Conclusões: O nosso trabalho confirma, na nossa população, o interesse preditivo de factores clínicos e anatomopatológicos normalmente associados a um comportamento biológico mais agressivo. Também sugere o interesse preditivo de alguns factores anatomopatológicos menos estudados. Por fim aponta para a possibilidade, de associação entre o fenómeno de transição epitelial e a ocorrência de RBQ.
Predictive value of epithelial-‐mesenchymal transition markers, PTEN, ERG, Ki67, and genetic analysis in biochemical recurrence of prostate cancer treated with surgery Introduction: Prostate cancer is a contemporary health issue. It has a very high incidence and prevalence. The majority of patients with localized disease are cured with current standard therapeutic options. Nevertheless, disease recurrence is associated with morbidity, mortality and significant costs. It is, therefore, important to optimize therapeutic efficacy. One of the possibilities to achieve it, is through better understanding of predictive factors. Pinpointing in advance, the cases with worse prognosis, could allow a therapeutic adjustment, by adding adjuvant treatment. Methods: In a clinical cohort study, we evaluated the predictive impact of several clinical, pathological and molecular factors in the development of biochemical recurrence (BCR), in patients with localized prostate cancer treated with radical prostatectomy. Results: A total of 147 patients were included in our study. The median follow-‐up time was 20 months. BCR occurred in 15.6% of the patients. In univariate analysis, pre-‐operative PSA (p=0.02); the type of surgery (p=0.01); the Gleason score both in biopsy (p=0.004) and in the index lesion (p<0.001); the Epstein grading system in the biopsy (p=0.005), in the entire tumor (p=0.006), and in the index lesion (p<0.001); the number of positive cores in the biopsy (p=0.05), the maximum length of cancer in any one biopsy core (p=0.01) and the greatest percentage of cancer in any biopsy core (p=0.02); the presence of intraductal differentiation in the prostatic specimen (p=0.003); the presence of a minor high-‐grade pattern (p<0.001); the index lesion dimension (p=0.005); positive surgical margin (p=0.05); the existence of extra prostatic extension (p=0.02); vascular invasion (p=0.002); seminal vesicle invasion (p=0.01); the total number of lymph nodes retrieved in patients submitted to lymphadenectomy (p=0.01); T stage (p=0.02) and loss of E-‐Cadherine, were all predictive factors for BCR. In multivariate analysis, only the presence of intraductal differentiation (p=0.01), Epstein grading system in the index lesion (p<0.001), vascular invasion (p=0.02) and the total number of lymph nodes (p=0.05) remained independently predictive of BCR. The remaining epithelial-‐mesenchymal transition markers (N-‐Cadherine and Vimentine), PTEN, Ki-‐67 and ERG, were not predictive factors for BCR. Neither was SChLAP1 expression, both in tumoral and non-‐tumoral tissue. Conclusions: Our study, in this population, confirms the predictive impact of many well-‐established predictive factors. It also implies, that other less known pathological factors might also have predictive importance. Finally, it suggest the existence of a link between epithelial-‐mesenchymal transition and BCR.
Predictive value of epithelial-‐mesenchymal transition markers, PTEN, ERG, Ki67, and genetic analysis in biochemical recurrence of prostate cancer treated with surgery Introduction: Prostate cancer is a contemporary health issue. It has a very high incidence and prevalence. The majority of patients with localized disease are cured with current standard therapeutic options. Nevertheless, disease recurrence is associated with morbidity, mortality and significant costs. It is, therefore, important to optimize therapeutic efficacy. One of the possibilities to achieve it, is through better understanding of predictive factors. Pinpointing in advance, the cases with worse prognosis, could allow a therapeutic adjustment, by adding adjuvant treatment. Methods: In a clinical cohort study, we evaluated the predictive impact of several clinical, pathological and molecular factors in the development of biochemical recurrence (BCR), in patients with localized prostate cancer treated with radical prostatectomy. Results: A total of 147 patients were included in our study. The median follow-‐up time was 20 months. BCR occurred in 15.6% of the patients. In univariate analysis, pre-‐operative PSA (p=0.02); the type of surgery (p=0.01); the Gleason score both in biopsy (p=0.004) and in the index lesion (p<0.001); the Epstein grading system in the biopsy (p=0.005), in the entire tumor (p=0.006), and in the index lesion (p<0.001); the number of positive cores in the biopsy (p=0.05), the maximum length of cancer in any one biopsy core (p=0.01) and the greatest percentage of cancer in any biopsy core (p=0.02); the presence of intraductal differentiation in the prostatic specimen (p=0.003); the presence of a minor high-‐grade pattern (p<0.001); the index lesion dimension (p=0.005); positive surgical margin (p=0.05); the existence of extra prostatic extension (p=0.02); vascular invasion (p=0.002); seminal vesicle invasion (p=0.01); the total number of lymph nodes retrieved in patients submitted to lymphadenectomy (p=0.01); T stage (p=0.02) and loss of E-‐Cadherine, were all predictive factors for BCR. In multivariate analysis, only the presence of intraductal differentiation (p=0.01), Epstein grading system in the index lesion (p<0.001), vascular invasion (p=0.02) and the total number of lymph nodes (p=0.05) remained independently predictive of BCR. The remaining epithelial-‐mesenchymal transition markers (N-‐Cadherine and Vimentine), PTEN, Ki-‐67 and ERG, were not predictive factors for BCR. Neither was SChLAP1 expression, both in tumoral and non-‐tumoral tissue. Conclusions: Our study, in this population, confirms the predictive impact of many well-‐established predictive factors. It also implies, that other less known pathological factors might also have predictive importance. Finally, it suggest the existence of a link between epithelial-‐mesenchymal transition and BCR.
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Carcinoma da próstata Prostatectomia radical Factor preditivo Classificação de Epstein Lesão Índice Carcinoma intraductal Invasão vascular Número de gânglios linfáticos caderina E Prostate cancer Radical prostatectomy Predictive factor Epstein grading Index lesion Vascular invasion Intraductal carcinoma Lymph node number E-‐cadherine