Impacto do rastreamento genético em crianças e adultos jovens com neoplasia endócrina múltipla tipo 2A : vinte anos de experiência de um centro de referência

O rastreamento genético identifica carreadores assintomáticos da mutação no proto-oncogene RET, que estão sob risco de desenvolver o câncer medular de tireoide (CMT) hereditário, possibilitando a tireoidectomia precoce e o aumento nas taxas de cura. Contudo, ainda existem controvérsias sobre o momento ideal da realização da tireoidectomia profilática. O objetivo deste estudo é descrever os achados clínicos e oncológicos dos carreadores da mutação no proto-oncogene RET diagnosticados na infância e início da vida adulta em acompanhamento na nossa instituição, bem como avaliar o impacto da idade da tireoidectomia no status da doença a longo prazo e quais os fatores associados a doença persistente. Foi realizado um estudo de coorte incluindo pacientes com NEM2A diagnosticados com idade menor ou igual a 25 anos. Os dados foram obtidos através de revisão de prontuários médicos. O desfecho primário foi o status da doença ao final do seguimento, classificado em resposta excelente, resposta bioquímica, resposta estrutural ou óbito. Foram incluídos 66 pacientes, sendo 47 (71.2%) diagnosticados pelo screening genético (grupo SG) e 19 (28.8%) diagnosticados através de doença clínica (grupo DC). A média de idade ao diagnóstico foi de 12.6 ± 6.7 anos e 65.2% eram do sexo feminino. A mutação mais frequente foi no codon 634, correspondendo a 84.8% dos casos. A mediana (p25-75) da calcitonina basal foi de 29.0 pg/mL (7.4 – 71.6 pg/mL). Cinquenta e oito pacientes foram submetidos à tireoidectomia total, enquanto oito pacientes estão em seguimento clínico. A idade média (±DP) da tireoidectomia foi maior no grupo DC (13.5 vs 18.1 anos, p 0.006). O tamanho do tumor variou de 0.1 a 3.5cm, com uma mediana 2.0cm (0.5-2.7) no grupo DC vs 0.6cm (0.3-1.0) no grupo SG – p0.052. Em relação ao TNM (8ª edição), 40 (75.4%) pacientes tinham doença estagio I, 6 (11.3%) estagio II, 1 (1.9%) estagio III, 3 (5.7%) estagio IVA e 3 (5.7%) estagio IVC. Os dados de seguimento mostram que, após uma média de 13.1 ± 7.8 anos de acompanhamento, 94.7% dos pacientes do grupo SG encontram-se livres de doença baseados no exame físico, ecografia cervical e níveis indetectáveis de calcitonina sérica. No grupo DC, 10/17 (58.8%) pacientes foram classificados com resposta excelente, 1 (5.9%) resposta bioquímica, 5 (29.4%) doença estrutural e 1 (5.9%) paciente foi a óbito. Análise da curva ROC para avaliar a performance da calcitonina pré-operatória (preCTN) como preditor de doença persistente resultou em uma área sob a curva de 0.87 [IC 0.75–0.99], e um valor de preCTN 42.5 pg/mL foi determinado como melhor ponto de corte com sensibilidade de 100% e especificidade de 69%. Em conclusão, apesar de nossos pacientes terem sido submetidos à tireoidectomia em uma idade mais tardia do que a recomendada pelas diretrizes atuais, a maioria se encontra livre de doença após um tempo de seguimento prolongado. Sabendo que a evolução da doença apresenta características individuais, nossos resultados reforçam a possibilidade de retardar o tratamento cirúrgico em pacientes carreadores da mutação RET que possuam níveis baixos de calcitonina sérica.Genetic screening Genetic screening allows the identification of asymptomatic carriers at risk of developing hereditary medullary thyroid carcinoma and early thyroidectomy, increasing cure rates. However, there are still controversies about the ideal timing of prophylactic thyroidectomy. The aim of this study is to describe the clinical and oncological findings of RET mutation carriers diagnosed in childhood and early adulthood, as well as to assess the impact of thyroidectomy age on long-term disease status and what are the factors associated with persistent disease. A cohort study including patients with MEN2A diagnosed aged 25 years or less was performed. Data were obtained through a review of medical records. The primary outcome was disease status at the end of follow-up, classified as excellent response, biochemical response, structural response, or death. A total of 66 patients were included, 47 (71.2%) diagnosed by genetic screening (GS group) and 19 (28.8%) diagnosed through clinical disease (CD group). The mean age at diagnosis was 12.6 ± 6.7 years and 65.2% were female. The most frequent mutation was at codon 634, corresponding to 84.8% of cases. The median (p25-75) of basal calcitonin was 29.0 pg/ml (7.4 – 71.6 pg/ml). Fifty-eight patients underwent total thyroidectomy, while eight patients are in clinical follow-up. The mean age (±SD) of total thyroidectomy was higher in the CD group (13.5 vs 18.1 years, p 0.006). Tumor size ranged from 0.1 to 3.5cm with median 2.0cm (0.5-2.7) in CD group vs 0.6cm (0.3-1.0) in GS group – p0.052. Regarding the TNM (8th edition), 40 (75.4%) patients had stage I disease, 6 (11.3%) stage II, 1 (1.9%) stage III, 3 (5.7%) stage IVA and 3 (5.7%) stage IVC. Follow-up data show that, after a mean of 13.1 ± 7.8 years of follow-up, 94.7% of patients in the SG group are disease-free based on physical examination, cervical ultrasound, and undetectable serum calcitonin levels. In the CD group, 10/17 (58.8%) patients were classified as having an excellent response, 1 (5.9%) biochemical response, 5 (29.4%) structural disease and 1 (5.9%) patient died. ROC curve analysis to assess the performance of preoperative calcitonin (preCTN) as a predictor of persistent disease resulted in an area under the curve of 0.87 [CI 0.75–0.99], and a preCTN value of 42.5 pg/mL was determined to be best cut-off point with 100% sensitivity and 69% specificity. In conclusion, although our patients underwent thyroidectomy later than recommended by current guidelines, most are disease-free after prolonged follow-up. Knowing that the evolution of the disease has individual characteristics, our results reinforce the possibility of delaying surgical treatment in patients carrying the RET mutation who have low levels of serum calcitonin

Effect of suppressive levothyroxine therapy on bone mineral density in young patients with differentiated thyroid carcinoma

Suppressive levothyroxine therapy (sT4) is a cornerstone in the management of differentiated thyroid cancer (DTC). Long-term sT4 may affect bone mineral density (BMD). We evaluated the effect of sT4 on the bone mass of young DTC patients. In this cross-sectional study, BMD was evaluated via dual-energy X-ray absorptiometry in DTC patients younger than 25 years at diagnosis and undergoing sT4 for ≥1 year. The two control groups comprised patients matched for sex, age, and body-mass-index who were thyroidectomized for indications other than DTC and undergoing L-T4-replacement therapy, and healthy individuals with no prior known thyroid disease. Ninety-three participants were included (thirty-one in each group). There were no differences in the mean age, female sex (77.4% in all groups), or BMI between the sT4 group and each control group. The median TSH level was lower (0.4 [0.04–6.5] vs. 2.7 [0.8–8.5] mIU/mL, p = 0.01) and the mean L-T4 mcg/Kg levels were higher (2.4 ± 0.6 vs. 1.6 ± 0.3, p = 0.01) in the sT4 group compared to the L-T4-replacement therapy group. Lumbar spine, femoral neck, and total femur BMD were all similar among the groups. sT4 does not impact BMD in young DTC patients after a median time of suppression of 8 years. These findings may help in the decision-making and risk/benefit evaluation of sT4 for this population

Effect of Suppressive Levothyroxine Therapy on Bone Mineral Density in Young Patients with Differentiated Thyroid Carcinoma

Suppressive levothyroxine therapy (sT4) is a cornerstone in the management of differentiated thyroid cancer (DTC). Long-term sT4 may affect bone mineral density (BMD). We evaluated the effect of sT4 on the bone mass of young DTC patients. In this cross-sectional study, BMD was evaluated via dual-energy X-ray absorptiometry in DTC patients younger than 25 years at diagnosis and undergoing sT4 for ≥1 year. The two control groups comprised patients matched for sex, age, and body-mass-index who were thyroidectomized for indications other than DTC and undergoing L-T4-replacement therapy, and healthy individuals with no prior known thyroid disease. Ninety-three participants were included (thirty-one in each group). There were no differences in the mean age, female sex (77.4% in all groups), or BMI between the sT4 group and each control group. The median TSH level was lower (0.4 [0.04–6.5] vs. 2.7 [0.8–8.5] mIU/mL, p = 0.01) and the mean L-T4 mcg/Kg levels were higher (2.4 ± 0.6 vs. 1.6 ± 0.3, p = 0.01) in the sT4 group compared to the L-T4-replacement therapy group. Lumbar spine, femoral neck, and total femur BMD were all similar among the groups. sT4 does not impact BMD in young DTC patients after a median time of suppression of 8 years. These findings may help in the decision-making and risk/benefit evaluation of sT4 for this population