The BRAFV600E mutation analysis and risk stratification in papillary thyroid carcinoma

ABSTRACT Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively. The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients.

The rare intracellular RET mutation p.Ser891Ala in an apparently sporadic medullary thyroid carcinoma: a case report and review of the literature / Rara mutação intracelular p.Ser891Ala do RET em carcinoma medular de tireoide aparentemente esporádico: relato de caso e revisão da literatura

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from parafollicular C-cells and accounts for 4-10% of all thyroid carcinomas. MTC develops in either sporadic (75%) or hereditary form (25%). Mutations in the RET proto-oncogene are responsible for hereditary MTC and the rate of heritable disease among apparently sporadic MTC (sMTC) cases varies from 6 to 15%. RET genetic testing is now considered fundamental in MTC management but the extent of the molecular analysis required to exclude inherited disease is still controversial. While the screening of all known mutation loci is recommended by some authors, the high costs associated with a full analysis should be also taken into consideration. Here, we illustrate and discuss this controversial issue by reporting a patient who present all characteristic features of sMTC, and in whom a standard genetic analysis by restriction enzyme restriction excluded hereditary disease. Nevertheless, an extensive molecular analysis that included all codons was prompted by the diagnosis of thyroid neoplasm in a patient's sister, and identified the rare intracellular RET p.Ser891Ala mutation. Arq Bras Endocrinol Metab. 2012;56(8):586-91.

O carcinoma medular de tireoide (CMT) é um tumor maligno originado das células C parafoliculares e corresponde a 4-10% de todos os carcinomas de tireoide. O CMT se desenvolve ou de forma esporádica (75%) ou hereditária (25%). As mutações no proto-oncogene RET são responsáveis pelo CMT hereditário, e a ocorrência de doença hereditária entre casos aparentemente esporádicos de CMT varia de 6 a 15%. A avaliação genética do RET é considerada fundamental no manejo do CMT, mas a extensão de análise molecular necessária para se excluir a doença hereditária ainda é controversa. Embora a avaliação de todos os loci de mutação conhecidos seja recomendada por alguns autores, os altos custos associados com a análise completa devem ser considerados. Neste relato, ilustramos e discutimos esse assunto controverso por meio do caso de um paciente que apresentou todas as características clássicas de CMT esporádico e no qual a análise genética por restrição enzimática excluiu a doença hereditária. No entanto, devido ao diagnóstico de uma neoplasia de tireoide em uma irmã do paciente, foi indicada uma análise molecular mais extensa que identificou a rara mutação intracelular p.Ser891Ala no proto-oncogene RET. Arq Bras Endocrinol Metab. 2012;56(8):586-91.

Is there a role for inherited TR βmutation in human carcinogenesis? / Qual o papel da mutação do TR β na carcinogênese da tireoide em humanos?

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disorder characterized by end-organ reduced sensitivity to thyroid hormone. This syndrome is caused by mutations of the thyroid hormone receptor (TR) β gene, and its clinical presentation is quite variable. Goiter is reported to be the most common finding. A close association of TRβ mutations with human cancers has become apparent, but the role of TRβ mutants in the carcinogenesis is still undefined. Moreover, higher TSH levels, described in RTH syndrome, are correlated with increased risk of thyroid malignancy, whereas TSH receptor stimulation is likely to be involved in tumor progression. We report here an illustrative case of a 29 year-old patient with RTH caused by a mutation in exon 9 (A317T) of TRβ gene, who presented multicentric papillary thyroid cancer. We review the literature on this uncommon feature, and discuss the potential role of this mutation on human tumorigenesis, as well as the challenges in patient follow-up.

A síndrome da resistência aos hormônios tireoidianos (RHT) é caracterizada por redução da sensibilidade aos hormônios da tireoide. A apresentação clínica é variável, sendo a presença de bócio a manifestação mais frequentemente descrita. A associação de mutação no receptor β e neoplasias em humanos vem sendo demonstrada recentemente, porém o mecanismo pelo qual a mutação desse receptor está envolvida na carcinogênese não está completamente definido. Além disso, níveis elevados de TSH sérico, descritos na RHT, estão associados a aumento do risco de câncer de tireoide, e o estímulo do TSH está provavelmente envolvido na patogênese desses carcinomas. Este artigo relata o caso de um homem de 29 anos com RHT, com análise molecular demonstrando mutação no éxon 9, códon 317, e carcinoma papilar de tireoide. Revisamos a literatura dos casos relatados os quais descrevem associação entre RHT e câncer de tireoide e discutimos os desafios do tratamento e seguimento desses pacientes.