Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Is thyroid stunning clinically relevant? A retrospective analysis of 208 patients.

OBJECTIVE: Current guidelines have advised against the performance of (131)I-iodide diagnostic whole body scintigraphy (dxWBS) to minimize the occurrence of stunning, and to guarantee the efficiency of radioiodine therapy (RIT). The aim of the study was to evaluate the impact of stunning on the efficacy of RIT and disease outcome. SUBJECTS AND METHODS: This retrospective analysis included 208 patients with differentiated thyroid cancer managed according to a same protocol and followed up for 12-159 months (mean 30 ± 69 months). Patients received RIT in doses ranging from 3,700 to 11,100 MBq (100 mCi to 300 mCi). Post-RIT-whole body scintigraphy images were performed 10 days after RIT in all patients. In addition, images were also performed 24-48 hours after therapy in 22 patients. Outcome was classified as no evidence of disease (NED), stable disease (SD) and progressive disease (PD). RESULTS: Thyroid stunning occurred in 40 patients (19.2%), including 26 patients with NED and 14 patients with SD. A multivariate analysis showed no association between disease outcome and the occurrence of stunning (p = 0.3476). CONCLUSION: The efficacy of RIT and disease outcome do not seem to be related to thyroid stunning.

Is thyroid stunning clinically relevant? A retrospective analysis of 208 patients / O atordoamento da tireoide é clinicamente relevante? Análise retrospectiva de 208 pacientes

Objective : Current guidelines have advised against the performance of 131I-iodide diagnostic whole body scintigraphy (dxWBS) to minimize the occurrence of stunning, and to guarantee the efficiency of radioiodine therapy (RIT). The aim of the study was to evaluate the impact of stunning on the efficacy of RIT and disease outcome.Subjects and methods : This retrospective analysis included 208 patients with differentiated thyroid cancer managed according to a same protocol and followed up for 12-159 months (mean 30 ± 69 months). Patients received RIT in doses ranging from 3,700 to 11,100 MBq (100 mCi to 300 mCi). Post-RIT-whole body scintigraphy images were performed 10 days after RIT in all patients. In addition, images were also performed 24-48 hours after therapy in 22 patients. Outcome was classified as no evidence of disease (NED), stable disease (SD) and progressive disease (PD).Results : Thyroid stunning occurred in 40 patients (19.2%), including 26 patients with NED and 14 patients with SD. A multivariate analysis showed no association between disease outcome and the occurrence of stunning (p = 0.3476).Conclusion : The efficacy of RIT and disease outcome do not seem to be related to thyroid stunning. Arq Bras Endocrinol Metab. 2014;58(3):292-300.

Objetivo : As diretrizes atuais alertam contra a execução da cintigrafia de corpo inteiro com iodo-131 (dxWBS) para minimizar a ocorrência de atordoamento e garantir a eficiência do tratamento com radioiodo (RIT). O objetivo deste estudo foi avaliar o impacto do atordoamento sobre a eficácia do RIT e desfechos da doença.Sujeitos e métodos : Esta análise retrospectiva incluiu 208 pacientes com câncer diferenciado de tireoide submetidos ao mesmo protocolo e acompanhados por 12-159 semanas (média de 30 ± 69 meses). Os pacientes receberam RIT com doses variando de 3.700 a 11.100 MBq (100 mCi a 300 mCi). As imagens da cintigrafia após a RIT foram feitas 10 dias depois da RIT em todos os pacientes. Além disso, as imagens foram também obtidas após 24-48h em 22 pacientes. O desfecho foi classificado como nenhuma evidência de doença (NED), doença estável (SD) e doença progressiva (PD).Resultados : O atordoamento da tireoide ocorreu em 40 pacientes (19,2%), incluindo 26 pacientes com NED e 14 pacientes com SD. A análise multivariada não mostrou associação entre o desfecho da doença e a ocorrência de atordoamento (p = 0,3476).Conclusão : A eficácia da RIT e o desfecho da doença não parecem estar relacionados com o atordoamento da tireoide. Arq Bras Endocrinol Metab. 2014;58(3):292-300.

Cumulative doses of radioiodine in the treatment of differentiated thyroid carcinoma: knowing when to stop / Doses cumulativas de iodo radioativo no tratamento do carcinoma diferenciado de tireoide: sabendo a hora de parar

OBJECTIVE: Evaluate the efficacy of cumulative doses (CDs) of 131I-iodide therapy (RIT) in differentiated thyroid cancer (DTC). SUBJECTS AND METHODS: The probability of progressive disease according to CDs was evaluated in patients < 45 years old and > 45 years old and correlated to tumor-node-metastasis (TNM), thyroglobulin values, histological types and variants, age, and zduration of the disease. RESULTS: At the end of a follow-up period of 69 ± 56 months, 85 out of 150 DTC patients submitted to fixed doses RIT had no evidence of disease, 47 had stable disease and 18 had progressive disease. Higher CDs were used in the more aggressive variants (p < 0.0001), higher TNM stages (p < 0.0001), and follicular carcinomas (p = 0.0034). Probability of disease progression was higher with CDs > 600 mCi in patients > 45 years old and with CDs > 800 mCi in patients < 45 years. CONCLUSION: Although some patients may still respond to high CDs, the impact of further RIT should be carefully evaluated and other treatment strategies may be warranted.

OBJETIVO: Avaliar a eficácia de doses cumulativas (DCs) da terapia com iodeto-131I (RIT) no câncer diferenciado de tiroide (CDT). SUJEITOS E MÉTODOS: A probabilidade de doença em progressão conforme a DC foi calculada em pacientes com idade < 45 e > 45 anos e correlacionada com o TNM, valores de tiroglobulina sérica, tipos histológicos e variantes, idade e tempo de doença. RESULTADOS: Ao final de um seguimento de 69 ± 56 meses, 85 dos 150 pacientes CDT submetidos a doses fixas de RIT não tinham evidência de doença, 47 tinham doença estável e 18, doença progressiva. DCs mais elevadas foram usadas nas variantes agressivas (p < 0,0001), maior estágio TNM (p < 0,0001) e nos carcinomas foliculares (p = 0,0034). A probabilidade de doença em progressão foi maior com DCs > 600 mCi em pacientes > 45 anos e com DCs > 800 mCi em pacientes < 45 anos. CONCLUSÃO: Apesar de alguns pacientes ainda responderem a altas DCs, o impacto de RITs deve ser cuidadosamente avaliado e outras estratégias terapêuticas devem ser consideradas.

Cumulative doses of radioiodine in the treatment of differentiated thyroid carcinoma: knowing when to stop.

OBJECTIVE: Evaluate the efficacy of cumulative doses (CDs) of 131I-iodide therapy (RIT) in differentiated thyroid cancer (DTC). SUBJECTS AND METHODS: The probability of progressive disease according to CDs was evaluated in patients < 45 years old and > 45 years old and correlated to tumor-node-metastasis (TNM), thyroglobulin values, histological types and variants, age, and zduration of the disease. RESULTS: At the end of a follow-up period of 69 ± 56 months, 85 out of 150 DTC patients submitted to fixed doses RIT had no evidence of disease, 47 had stable disease and 18 had progressive disease. Higher CDs were used in the more aggressive variants (p < 0.0001), higher TNM stages (p < 0.0001), and follicular carcinomas (p = 0.0034). Probability of disease progression was higher with CDs > 600 mCi in patients > 45 years old and with CDs > 800 mCi in patients < 45 years. CONCLUSION: Although some patients may still respond to high CDs, the impact of further RIT should be carefully evaluated and other treatment strategies may be warranted.

Role of the N-acetyltransferase 2 detoxification system in thyroid cancer susceptibility.

PURPOSE: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility. EXPERIMENTAL DESIGN: We conducted a prospective case-control study, comparing 195 patients presenting with DTC that were previously genotyped for GSTT1, GSTM1, GSTP1, and CYP1A1, comprising 164 papillary carcinomas and 31 follicular carcinomas, with 196 control individuals paired for gender, age, ethnicity, diet routine, lifetime occupational history, smoking history, general health conditions, and previous diseases. We used PCR-RFLP assays and the combination of 6 variant alleles to define 18 NAT2 haplotypes that characterized slow, intermediate, or rapid phenotypes. RESULTS: A multivariate logistic regression analysis identified the presence of *12A and the absence of *12B, *13, *14B, *14D, *6A, and *7A NAT2 haplotypes as risk factors for DTC. The inheritance of a rapid acetylation phenotype doubled the risk for a papillary carcinoma (odds ratio, 2.024; 95% confidence interval, 1.252-3.272). We found no relationship between genotypes and clinical, pathologic, or laboratory features of patients or between genotypes and outcome. CONCLUSIONS: We showed that NAT2 genotypes and the NAT2 rapid acetylation phenotype are important susceptibility factors for DTC, suggesting that NAT2 detoxification system is involved in this tumor pathogenesis.

Identifying a risk profile for thyroid cancer.

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patients laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.

Identifying a risk profile for thyroid cancer

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patientÆs laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.

O uso cada vez mais freqüente de métodos diagnósticos simples e efetivos tem contribuído significativamente para um aumento no diagnóstico de câncer da tiróide nos últimos anos. Entretanto, existem importantes evidências de que muitos dos microcarcinomas papilíferos têm um comportamento indolente e podem nunca evoluir para cânceres clínicos. Existe, portanto, uma necessidade urgente de desenvolver novas ferramentas capazes de predizer quais os tumores tiroidianos que permanecerão silenciosos e quais desenvolverão comportamento agressivo. Há uma série de marcadores clínicos de evolução bem estabelecidos e alguns estudos recentes sugerem que dados laboratoriais e métodos de imagem podem ser úteis. Marcadores moleculares também vêm sendo ativamente investigados e alguns, como BRAF, os genes GST e polimorfismos de p53, parecem promissores. Além disso, marcadores imunocitoquímicos e a medida da natureza fractal da cromatina podem aumentar a especificidade do diagnóstico anatomopatológico e ajudar a predizer o prognóstico. Existe uma necessidade imperiosa de elaborarmos diretrizes destinadas a selecionar os nódulos que merecem prosseguimento em sua avaliação, assim como novos métodos capazes de identificar lesões mais agressivas entre os geralmente indolentes tumores tiroidianos.

Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants.

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

[Low-risk differentiated thyroid carcinoma--literature review and management guidelines]. / Câncer diferenciado da tiróide de baixo risco--revisão do estado atual da literatura e proposta de conduta.

The trend of increasing thyroid cancer has been recognized in Brazil as well as all over the world for several decades. The large use of simple and effective diagnostic tools has significantly contributed to this trend. It is estimated that small carcinomas found at surgery for benign thyroid disorders and by ultrasonography will be identified at greater frequency in the further years. Part of these tumors occurs in low-risk patients that may benefit of less aggressive management strategies. However, the characterization of low-risk patient is still confusing and we lack adequate markers to tell apart patients that may present a troublesome progression of the disease. Furthermore, the use of new follow-up methods has recently changed some guidelines. A multidisciplinary team, including basic scientists, endocrinologists, nuclear medicine physicians, thyroid surgeons and endocrine pathologists reviewed the pertinent literature and, based on their experience, propose some management guidelines for Brazilian patients with low-risk thyroid carcinomas.

Câncer diferenciado da tiróide de baixo risco: revisão do estado atual da literatura e proposta de conduta / Low-risk differentiated thyroid carcinoma: literature review and management guidelines

A incidência do câncer diferenciado da tiróide vem aumentando há várias décadas no Brasil, assim como em todo o mundo. A popularização de métodos diagnósticos sensíveis e de uso relativamente simples tem contribuído para o diagnóstico cada vez mais freqüente de carcinomas de pequeno tamanho. Uma parte destes tumores ocorre em pacientes denominados de baixo risco, que poderiam se beneficiar de estratégias de conduta menos agressivas. Entretanto, a definição de baixo risco ainda é confusa e não existem meios seguros para distinguir os pacientes que evoluirão de forma pior dos demais. Por outro lado, o uso de novos métodos de acompanhamento vem mudando a maneira de conduzir estes casos. Um grupo multidisciplinar que inclui pesquisadores básicos, endocrinologistas, médicos nucleares, cirurgiões e patologistas endócrinos reviu a literatura pertinente e, com base em sua experiência, propõe algumas normas de conduta no carcinoma diferenciado da tiróide chamado de baixo risco em nosso meio.

[Thyroid cancer: prognostic factors and treatment]. / Câncer diferenciado da tiróide: fatores prognósticos e tratamento.

Because most differentiated thyroid carcinomas have an excellent prognosis, some authors have claimed that these patients are suffering from over treatment. Grouping patient- and tumor-specific factors have been proposed for prognostic stratification, but no clinicopathologic staging was demonstrated to be useful at the present time. More recently, molecular genetic tools have been used to identify and understand how the primary tumor progresses and many molecular markers have been proposed in order to distinguish the subset of patients at risk of developing metastasis. Here we analyzed some of them, with emphasis on the expression of NIS, a determinant of prognosis since the functional integrity of the iodine transport is essential to assure an uptake of radioiodine high enough to detect and destroy any tumoral thyroid tissue. More recent observations on how some relevant molecular genetics aspects of thyroid cancer impact new potential therapeutic approaches are also discussed.

Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid cancer.

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer.

GST profiling may be useful in the screening for thyroid nodule malignancy.

Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001 The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening.

Câncer diferenciado da tiróide: fatores prognósticos e tratamento / Thyroid cancer: prognostic factors and treatment

Como a maior parte dos carcinomas diferenciados tem um excelente prognóstico, alguns autores têm considerado o tratamento convencional, isto é, a tiroidectomia total seguida de ablação actínica de remanescentes glandulares, excessivo. Combinações de fatores específicos do paciente e do tumor têm sido propostas para classificação prognóstica, mas nenhum estadiamento clinicopatológico foi implantado na prática clínica até o momento. Mais recentemente, técnicas de genética molecular têm sido empregadas na compreensão e identificação dos mecanismos envolvidos na progressão do tumor primário. Marcadores moleculares, em adição aos clinicopatológicos, vêm sendo propostos para identificar os pacientes de alto risco. Apresentamos alguns deles, com ênfase na expressão de NIS, um óbvio determinante de prognóstico, já que a integridade funcional do sistema de transporte de iodo é essencial para o reconhecimento e destruição de tecido tiroidiano. Tecemos breves comentários sobre a aplicação dos novos conhecimentos da genética molecular do câncer da tiróide em diferentes alternativas terapêuticas.

Low expression of sodium iodide symporter identifies aggressive thyroid tumors.

A decreased radioiodine uptake is frequently detected in differentiated thyroid carcinomas (DTC) and is associated with high recurrence rate and reduced survival. We investigated the correlation between NIS mRNA expression levels in the primary tumor and patient outcome using a quantitative real-time RT-PCR method. NIS expression was decreased in 17 DTC (21.04+/-39.66 pg Eq) compared to four autoimmune thyroid disease (180.51+/-92.63 pg Eq) and 14 normal tissues (75.71+/-66.98 pg Eq) (p<0.0001). The 17 thyroid differentiated carcinoma patients were submitted to surgery complemented by radioiodine ablation and had at least 24 months of follow-up, under levothyroxine continued suppressive therapy. According to their outcome, we could characterize a group of papillary carcinoma patients with aggressive carcinomas, whose NIS mRNA levels were markedly lower than a group with non-aggressive carcinomas (0.62+/-0.79 versus 54.87+/-53.79; p<0.005). We suggest that the quantification of NIS mRNA relative levels in the primary tumor may predict poor outcome.

Metástase de adenocarcinoma mamário para a hipófise: relato de caso / Breast adenocarcinoma metastatic to the pituitary gland: a case report

Relato de caso de metástase de adenocarcinoma mamário para a hipófise, referente a uma paciente de 57 anos de idade, apresentando imagem de tomografia computadorizada sugestiva de adenoma primário de hipófise. É mencionada pelos autores a importância da cirurgia no diagnóstico definitivo da lesao para determinar o tratamento apropriado.