RESUMO
Introdução: Cerca de 20% a 40% da população apresenta nódulos tireoidianos assintomáticos e, aproximadamente 30% destes nódulos apresentam malignidade ao exame anatomopatológico pós-cirúrgico. Tentativas de se estabelecer associações biológicas e diferenças entre os distúrbios benignos e malignos da tireóide mostram resultados conflitantes. Estudos prévios utilizando cDNA microarrays identificaram genes com expressão diferencial em diferentes patologias tireoidianas, incluindo IGFBP5; proteases como a catepsina B e inibidores de proteinases como a a1 antitripsina; componentes envolvidos nos processos de endocitose e transporte intracelular como a clatrina e; reguladores do ciclo celular como p27 e p21. Objetivo: analisar, caracterizar e comparar o perfil de expressão protéico de seis genes diferencialmente expressos em tireóide normal, bócio, adenoma folicular e carcinomas diferenciados e, determinar a importância clínica dos fenótipos identificados. Métodos: 172 amostras de tecido tireoidiano incluindo 18 normais, 18 bócios, 50 adenomas foliculares, 50 carcinomas papilíferos e 36 carcinomas foliculares foram coletadas em duplicata para análise e comparação dos padrões de expressão de seis proteínas (p27, p21, IGFBP5, clatrina, a1-antitripsina e catepsina B) utilizando técnicas de imunoistoquímica em tissue microarrays. Os casos foram avaliados de acordo com a intensidade da coloração (O a 4) e porcentagem de células positivas (O a 4). Resultados: Foi observada expressão diferencial para alfa 1 antitripsina, clatrina e IGFBP5, p21 e p27 quando os tecidos foram comparados (p< 0,0001 ). Tecidos neoplásicos exibem expressão aumentada de IGFBP5 em relação aos não neoplásicos. Nenhuma diferença significativa foi observada em relação à expressão de catepsina B. Nas células foliculares normais e de bócio, a imunorreatividade para p27 e p21 foi predominantemente nuclear em comparação aos carcinomas. Este mesmo padrão foi observado em adenoma quando comparados aos carcinomas foliculares (p< 0,008). Carcinomas papilíferos exibiram expressão citoplasmática aumentada de p27 e p21. Conclusão: Vários e novos genes detectados por técnicas de análise genômica em larga escala podem estar envolvidos na patogênese molecular e progressão tumoral. A transcrição destes genes pode resultar na superexpressão de proteínas como IGFBP5, clatrina e alfal antitripsina, enquanto modificações pós-transcricionais resultam em alteração da expressão de proteínas nucleares envolvidas no controle do ciclo celular e, que contribuem para o processo de malignização da tireóide. Dados obtidos em TMA são consistentes com os resultados obtidos por cDNA microarray mostrando expressão protéica diferencial para p27, p21, IGFBP5, clatrina e al-antitrpsina em tecido tireoidiano normal, hiperplásico e neoplásico; o que poderia ser de valor diagnóstico e prognóstico.
Introduction: Thyroid nodules can be detected in 20%-40% of asymptomatic patients and, in 30% of them, malignant disease can be found by histopathology of post-surgical tissue samples. Attempts to establish biological links and differences between benign and malignant thyroid disorders have shown conflicting results. Previous studies using cDNA microarrays have identified genes with differential expression in thyroid diseases, including IGFBP5; proteases such as cathepsin B and proteinase inhibitors as alpha-1 antitrypsin; components involved in endocitose and intracellular transportation such as clathrin, and; cell cycle regulators such as p27 and p21. Purpose: to analyze, characterize and compare the protein expression profile of six genes differentially expressed in normal thyroid, goiter, follicular adenomas, and differentiated carcinomas, and ultimately, evaluate the clinicai importance o f the identified phenotypes. Methods: Samples of 172 tissues including 18 normal thyroids, 18 goiters, 50 follicular adenomas, 50 papillary carcinomas and 36 follicular carcinomas were collected in duplicates for analysis and comparison of six proteins expression pattems (p27, p21, clathrin, IGFBP5, alpha 1 antitrypsin and cathepsin B) using immunohistochemistry and tissue microarrays techniques. Cases were scored in relation to intensity of staining (O to 4) and number of stained cells (O to 4). Results: We found differential expression for a1-anti-tripsin, clathrin, IGFBP5, p21 and p27 when tissues were compared (p<0.0001). IGFBP5 expresswn was elevated in all neoplastic compared to non-neoplastic tissues. No significant differences were observed for cathepsin B. In normal and goiter follicular cells, immunostaining of p27 and p21 was predominantly nuclear when compared to carcinoma cells. The same pattem of expression was noted for follicular adenomas when compared to follicular carcinomas (p<0.008). Papillary carcinomas displayed a predominant diffuse cytoplasmatic p27 and p2l staining when compared to nonmalignant tissues. Conclusion: Severa! genes and new ones detected by highthroughput genomic profiling may be involved in molecular pathogenesis and tumoral progression. Transcription of these genes may result in overexpression of proteins like IGFBP5, clathrin and alpha 1 antitrypsin, while post-transcriptional changes may result in altered expression of nuclear proteins involved in cell cycle regulation that may contribute to the thyroids carcinogenesis. TMA data are consistent with results obtained with cDNA microarray showing differential protein expression for p27, p21, IGFBP5, clathrin and al-AT in normal, hyperplastic and, neoplastic thyroid tissues which could be of diagnostic and prognostic.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Glândula Tireoide , Análise Serial de Tecidos , Neoplasias , Fenótipo , Neoplasias da Glândula Tireoide , Carcinoma , Adenoma , Carcinoma Papilar, Variante Folicular , Câncer Papilífero da Tireoide , Genes , BócioRESUMO
INTRODUCTION: In the postmenopausal period, an average of 25 percent of women will present symptomatic ovarian failure requiring hormonal replacement therapy. Estrogen can relieve vasomotor symptoms. Hormonal replacement therapy is generally not recommended for breast cancer patients due to the potential risk of tumor recurrence. To answer the questions about the safety of hormonal replacement therapy in this subgroup of women, it is necessary to establish the acceptance of treatment. METHODS: Between September 1998 and February 2001, a cohort of 216 breast cancer patients were asked to complete a questionnaire. All patients had completed their treatment and were informed about survival rates after breast cancer and hormonal replacement therapy. RESULTS: Among the 216 patients, 134 (62 percent) would refuse hormonal replacement therapy. A hundred patients were afraid of relapse (74.6 percent). Adjuvant tamoxifen therapy was the only statistically significant variable (70.3 percent versus 29.7 percent p=0.003). Understanding clinical stage (p= 0.045) and type of medical assistance (private versus public , p=0.033) also seemed to influence the decision. Early stage disease (p= 0.22), type of surgical procedure (radical versus conservative, p=0.67), adjuvant chemotherapy (p=0.082) or marital status (p=0.98 ) were not statistically significant in decision making. Several patients submitted to adjuvant chemotherapy (41.6 percent) would accept hormonal replacement therapy under medical supervision, as did most of advanced clinical stage patients (58.3 percent; p=0.022). CONCLUSION: There is a high level of rejection for hormonal replacement therapy among breast cancer patients when current data on tumor cure rates, and potential risks of estrogen use is available. Adverse effects of tamoxifen in the adjuvant setting may be the reason for refusal of hormonal replacement therapy