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Background: The diagnosis of cancer in Bethesda III/IV thyroid nodules is challenging as fine-needle aspiration (FNA) has limitations, and these cases usually require diagnostic surgery. As approximately 77% of these nodules are not malignant, a diagnostic test accurately identifying benign thyroid nodules can reduce "potentially unnecessary" surgery rates. We have previously reported the development and validation of a microRNA-based thyroid classifier (mir-THYpe) with high sensitivity and specificity, which could be performed directly from FNA smear slides. We sought to evaluate the performance of this test in real-world clinical routine to support clinical decisions and to reduce surgery rates., Methods: We designed a real-world, prospective, multicentre study. Molecular tests were performed with FNA samples prepared at 128 cytopathology laboratories. Patients were followed-up from March 2018 until surgery or until March 2020 (patients with no indication for surgery). The final diagnosis of thyroid tissue samples was retrieved from postsurgical anatomopathological reports., Findings: A total of 435 patients (440 nodules) classified as Bethesda III/IV were followed-up. The rate of avoided surgeries was 52·5% for all surgeries and 74·6% for "potentially unnecessary" surgeries. The test achieved 89·3% sensitivity, 81·65% specificity, 66·2% positive predictive value, and 95% negative predictive value. The test supported 92·3% of clinical decisions., Interpretation: The reported data demonstrate that the use of the microRNA-based classifier in the real-world can reduce the rate of thyroid surgeries with robust performance and support clinical decision-making., Funding: The São Paulo Research-Foundation (FAPESP) and Onkos., Competing Interests: Declaration of interests MTS holds equity at Onkos Molecular Diagnostics. BMR, SS, AFO and MO are formal employees at Onkos Molecular Diagnostics. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The risk of malignancy (RoM) of indeterminate thyroid nodules (ITNs) shows a high variability in interinstitutional cohorts. The RoM is partially associated with the cytological degree of atypia and the ultrasound (US) pattern. This study evaluated the cancer risk of ITNs by jointly considering the cytological subcategory and the American Thyroid Association (ATA)-based US risk classification. Methods: This study features a retrospective cohort from two Brazilian centers comprising 238 ITNs with confirmed outcomes. US classification, according to ATA-based guidelines, and cytological subcategorization were determined. The cytological subgroups were as follows: (1) nuclear atypia (NA) related to papillary thyroid carcinoma (PTC) but insufficient to categorize the cytology as suspicious for malignancy; (2) architectural atypia without NA (AA); (3) both architectural and nuclear atypia (ANA); (4) oncocytic pattern (OP) without NA; and (5) NA not related to PTC (NANP). NA was divided into three subgroups: nuclear size and shape, nuclear membrane appearance, and/or chromatin aspects. Results: The overall frequency of malignancy was 39.5%. Among the cytological subcategories, the highest RoM was related to the NA (43.9%) and to the ANA (43.5%), followed by AA (29.4%), and OP (9.4%). NA was positively and independently associated with cancer (odds ratio [OR]: 4.5; confidence interval [CI: 1.2-16.6]) as was the occurrence of ANA (OR 6.6 [CI 1.5-29.5]). AA and OP were not independently associated with cancer. Both ATA-based high- and intermediate-risk categories showed an independent association with cancer (OR 6.8 [CI 2.9-15.5] and OR: 2.6 [CI 1.1-5.8], respectively). ITNs with cytological findings of NA or ANA when combined with intermediate US patterns had RoM values of 47.5% and 56.7%, respectively. Both cytological subcategories, when combined with the ATA high-suspicion class reached an RoM >70%. The type of NA with the highest odds for cancer was related to the nuclear membrane (OR 11.5). Conclusions: The RoM of ITNs can reach almost 80% when both NA and ATA-based high-risk US features are present. The presence of such cytological features also increased the RoM in the ATA-based intermediate-risk US category. In addition, AA and OP were not independently related to higher cancer risk. These results strengthen the recommendations for combing cytological subcategorization and US risk classification in the workup for ITNs before the decision of a molecular testing, clinical observation, or diagnostic surgery.

The indolent evolution of low-risk papillary thyroid microcarcinoma (mPTC) in adult patients and the consequences of thyroidectomy require a revision of the management traditionally recommended. Aiming to spare patients unnecessary procedures and therapies and to optimize the health system in Brazil, we suggest some measures. Fine-needle aspiration of nodules ≤ 1 cm without extrathyroidal extension on ultrasonography should be performed only in nodules classified as "very suspicious" (i.e., high suspicion according to ATA, high risk according to AACE, TI-RADS 5) and in selected cases [age < 40 years, nodule adjacent to the trachea or recurrent laryngeal nerve (RLN), multiple suspicious nodules, presence of hypercalcitoninemia or suspicious lymph nodes]. Active surveillance (AS) rather than immediate surgery should be considered in adult patients with low-risk mPTC. Lobectomy is the best option in patients with unifocal low-risk mPTC who are not candidates for AS because of age, proximity of the tumor to the trachea or RLN, or because they opted for surgery. The same applies to patients who started AS but had a subsequent surgical indication not due to a suspicion of tumor extension beyond the gland or multicentricity. Molecular tests are not necessary to choose between AS and surgery or, in the latter case, between lobectomy and total thyroidectomy. The presence of RAS or other RAS-like mutations or BRAFV600E or other BRAF V600E-like mutations should not modify the management cited above; however, the rare cases of mPTC exhibiting high-risk mutations, like in the TERT promoter or p53, are not candidates for AS.

Objective: This study assessed whether or not a simple biochemical parameter, serum thyrotropin (TSH), within the reference range can predict the likelihood of thyroid malignancy in subjects undergoing fine-needle aspiration biopsy (FNAB) for thyroid nodules., Subjects and Methods: This cross-sectional study evaluated 236 patients without overt thyroid dysfunction who were not on levothyroxine therapy. They underwent FNAB of the thyroid nodules at the Clementino Fraga Filho University Hospital between 2011 and 2012. The reference range and serum TSH quartiles were determined according to age-specific values for serum TSH and then compared between the cases with benign thyroid nodular disease and differentiated thyroid carcinoma (DTC) based on surgical pathology reports., Results: Of the 236 patients, 201 (85.1%) underwent a surgical procedure (thyroidectomy) and 89/236 (44.3%) had DTC. The mean TSH concentrations were 2.09 ± 1.15 mU/L in benign patients versus 2.73 ± 1.33 mU/L in cases of DTC (p < 0.01). As TSH increased from quartiles 1 to 4, the frequency of a malignant diagnosis also increased progressively from 22% in quartile 1 to 65% in the last quartile (p ≤ 0.001)., Conclusion: Thyrotropin levels were positively associated with the diagnosis of DTC in thyroid nodules., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Objective: The aim of this study was to describe the ultrasound features of benign and malignant thyroid nodules and evaluate the likelihood of malignancy associated with each feature according to the Bethesda System for Reporting Thyroid Cytopathology and histopathology. With this analysis, we propose a new TI-RADS classification system., Materials and Methods: The likelihood of malignancy from ultrasound features were assessed in 1413 thyroid nodules according to the Bethesda System for Reporting Thyroid Cytopathology and histopathological findings. A score was established by attributing different weights to each ultrasound feature evaluated., Results: Features positively associated with malignancy in bivariate analysis received a score weight of +1. We attributed a weight of +2 to features which were independently associated with malignancy in a multivariate analysis and +3 for those associated with the highest odds ratio for malignancy (> 10.0). Hence, hypoechogenicity (graded as mild, moderate or marked, according to a comparison with the overlying strap muscle), microcalcification and irregular/microlobulated margin received the highest weights in our scoring system. Features that were negatively associated with malignancy received weights of -2 or -1. In the proposed system a cutoff score of 2 (sensitivity 97.4% and specificity 51.6%) was adopted as a transition between probably benign (TI-RADS 3) and TI-RADS 4a nodules. Overall, the frequency of malignancy in thyroid nodules according to the categories was 1.0% for TI-RADS 3, 7.8% for TI-RADS 4a, 35.3% for TI-RADS 4b, and 84.7% for TI-RADS 5., Conclusion: A newly proposed TI-RADS classification adequately assessed the likelihood of malignancy in thyroid nodules.

Background: The incidence of pediatric differentiated thyroid carcinoma (DTC) has been rising in recent years, and the main risk factors for recurrence are lymph node and distant metastasis at diagnosis. Other clinical features remain unclear, such as the impact of age, sex, and puberty. Furthermore, until now, this population has been treated using the same strategies used to treat adults. In 2015, the American Thyroid Association (ATA) published the first guidelines targeted at this age group. The aims of this study were to investigate the prognostic factors for early and long-term remission and also to validate the ATA risk stratification proposal in a population outside the United States., Methods: Clinical records from 118 patients <18 years old followed in two referral centers were reviewed. The median age was 12 years (range 4-18 years), and 20.3% (24 patients) were <10 years old at diagnosis. The median follow-up was 9.1 years. The majority were female (72%) and received total thyroidectomy and radioiodine therapy (RAI), and 61.8% were treated with more than one dose of RAI. The majority were classified as high risk (48.3%) by the new ATA pediatric guidelines due to distant metastasis (30 patients) or extensive lymph node involvement (27 patients). The remained were classified as low risk (31.3%) and intermediate risk (20.4%)., Results: Females with no lymph node or distant metastasis and low ATA pediatric risk were more likely to have no evidence of disease (p < 0.05) within the first year and also in the long term. In this study, age did not significantly predict outcomes. Furthermore, patients also benefitted from multiple doses of RAI, but when the cumulative activity was >400 mCi, this benefit was diminished., Conclusions: This study shows that the ATA risk stratification proposal for pediatric patients is useful in predicting early and long-term outcomes in pediatric patients with DTC. In addition, it shows that sex and metastatic disease are important prognostic factors in pediatric populations.

Thyroid nodules are frequent findings, especially when sensitive imaging methods are used. Although thyroid cancer is relatively rare, its incidence is increasing, particularly in terms of small tumors, which have an uncertain clinical relevance. Most patients with differentiated thyroid cancer exhibit satisfactory clinical outcomes when treatment is appropriate, and their mortality rate is similar to that of the overall population. However, relapse occurs in a considerable fraction of these patients, and some patients stop responding to conventional treatment and eventually die from their disease. Therefore, the challenge is how to identify the individuals who require more aggressive disease management while sparing the majority of patients from unnecessary treatments and procedures. We have updated the Brazilian Consensus that was published in 2007, emphasizing the diagnostic and therapeutic advances that the participants, representing several Brazilian university centers, consider most relevant in clinical practice. The formulation of the present guidelines was based on the participants' experience and a review of the relevant literature.

Introduction: Hyperthyroidism is characterized by increased synthesis and release of thyroid hormones by the thyroid gland. Thyrotoxicosis refers to the clinical syndrome resulting from excessive circulating thyroid hormones, secondary to hyperthyroidism or due to other causes. This article describes evidence-based guidelines for the clinical management of thyrotoxicosis., Objective: This consensus, developed by Brazilian experts and sponsored by the Department of Thyroid Brazilian Society of Endocrinology and Metabolism, aims to address the management, diagnosis and treatment of patients with thyrotoxicosis, according to the most recent evidence from the literature and appropriate for the clinical reality of Brazil., Materials and Methods: After structuring clinical questions, search for evidence was made available in the literature, initially in the database MedLine, PubMed and Embase databases and subsequently in SciELO - Lilacs. The strength of evidence was evaluated by Oxford classification system was established from the study design used, considering the best available evidence for each question., Results: We have defined 13 questions about the initial clinical approach for the diagnosis and treatment that resulted in 53 recommendations, including the etiology, treatment with antithyroid drugs, radioactive iodine and surgery. We also addressed hyperthyroidism in children, teenagers or pregnant patients, and management of hyperthyroidism in patients with Graves' ophthalmopathy and various other causes of thyrotoxicosis., Conclusions: The clinical diagnosis of hyperthyroidism usually offers no difficulty and should be made with measurements of serum TSH and thyroid hormones. The treatment can be performed with antithyroid drugs, surgery or administration of radioactive iodine according to the etiology of thyrotoxicosis, local availability of methods and preferences of the attending physician and patient.

Objectives: To evaluate the prevalence of goiter and nodular disease in patients with class III obesity, and to correlate results with serum leptin levels and insulin resistance (IR) parameters., Subjects and Methods: A cross-sectional study was performed to assess thyroid ultrasound (US) patterns, HOMA-IR, serum leptin, and TSH levels in obese patients and controls., Results: Thyroid volume was positively correlated with body mass index (BMI) (r = 0.240, p = 0.039) and with HOMA-IR (r = 0.329; p < 0.01). Thyroid US patterns were similar between groups. However, when data from the male group was considered, greater thyroid volume was detected in the obese group compared with controls (10.8 vs. 8.5 cm³; p = 0.04). Also, nodules were more frequently detected (67% vs. 18%), as were nodules requiring FNAB (33.3% vs. 0%, p ≥ 0.05-0.09), in this group., Conclusion: Although IR did not correlate directly with the presence of nodules, the results support the hypothesis of a direct association between insulin resistance and thyroid volume.

Several guidelines on diagnosis and treatment of thyroid nodules and cancer have recently been published. However, recommended practices are not always appropriate to different settings or countries. The aim of this consensus was to develop Clinical Guidelines for evaluation and management of patients with thyroid nodules applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society involved with research and management of thyroid nodules and cancer from different medical centers in Latin America. The consensus was produced based on the expert opinion of the panel with use of principles of evidence-based medicine. Following a group meeting, a first draft based on the expert opinion of the panel was elaborated and later circulated among panel members for further revision. After revision, this document was submitted to all LATS members for commentaries and considerations and finally revised and refined by the authors. The final recommendations represent state of the art on management of thyroid nodules applied to all Latin American countries.

Iodine incorporation into thyroglobulin is dependent on the activities of both thyroperoxidase (TPO) and thyroid dual oxidase 2 (DuOx2). Although TPO expression is decreased in some thyroid nodular lesions, DuOx1 and 2 mRNA expressions are maintained, but DuOx H2O2-generating activity has never been evaluated in such tumors. Our goal was to determine DuOx activity in hypofunctioning lesions of the thyroid. We evaluated H2O2 generation by DuOx in 12 paranodular to cold nodule samples, 17 non-toxic multinodular goiters (MNG; 33 samples), 3 papillary carcinomas (PC; 4 samples), 3 follicular carcinomas (FC; 4 samples), and 10 follicular adenomas. DuOx activity was detected in all paranodular tissues (121+/-23 nmol H2O2/h per mg protein), but was undetectable (<1 nmol H2O2 generated) in all PC, two out of four FC samples and seven out of ten adenomas. In 11 MNG at least two different areas of the goiter have been evaluated, and in 5 of these goiters one of the samples had DuOx activity below the limit of detection. The coefficient of variation in MNG samples ranged from 11.3 to 57.2%. Interestingly, in all the adenomas studied, TPO activity (486+/-142 U/g protein, n=8) was well within the range found in paranodular tissues (414+/-116 U/g protein, n=3). We found a significant negative correlation between DuOx and TPO activities, suggesting that these enzymes are regulated in opposite directions, at least in thyroid tumors.

Thyroid nodules are a common manifestation of thyroid diseases. It is estimated that approximately 10% of adults have palpable thyroid nodules with the frequency increasing throughout life. The major concern on nodule evaluation is the risk of malignancy (5-10%). Differentiated thyroid carcinoma accounts for 90% of all thyroid malignant neoplasias. Although most patients with cancer have a favorable outcome, some individuals present an aggressive form of the disease and poor prognostic despite recent advances in diagnosis and treatment. Here, a set of clinical guidelines for the evaluation and management of patients with thyroid nodules or differentiated thyroid cancer was developed through consensus by 8 member of the Department of Thyroid, Sociedade Brasileira de Endocrinologia e Metabologia. The participants are from different reference medical centers within Brazil, to reflect different practice patterns. Each committee participant was initially assigned to write a section of the document and to submit it to the chairperson, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. All committee members further revised and refined the document. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information.