mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression.

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.

The ETA-ESE statement on the European Chemicals Agency opinion on iodine as an endocrine disruptor.

In 2022, the European Chemicals Agency (ECHA) made a statement concluding that iodine is an endocrine disruptor (ED). "We stress the fact that the ECHA opinion ECHA/BPC/357/2022 is based on their misguidedly zooming in on exclusively the biocidal products (e.g., hand disinfectants, disinfection of animals' teats/udder, embalming fluids before cremation, etc.) that contain molecular iodine (I2), entirely neglecting [see the 2013 ECHA Regulation (EU) n°528/2012 describing iodine as being of "great importance for human health". Clearly, the current sweeping and erroneous classification of "iodine" as an endocrine disruptor is ill-advised. We moreover call upon the scientific and medical community at large to use the accurate scientific nomenclature, i.e., iodide or iodate instead of "iodine" when referring to iodized salts and food prepared there with. Drugs, diagnostic agents, and synthetic chemicals containing the element iodine in the form of covalent bonds must be correctly labelled ''iodinated'', if possible, using each time their distinctive and accurate chemical or pharmacological name.

Survey on selenium clinical supplementation in autoimmune thyroid disease.

Objective: Previous trials show that selenium could be a very useful tool in the control and treatment of autoimmune thyroid diseases. In this cross-sectional study, through a survey, we aim to evaluate Portuguese endocrinologists' perception and pattern of prescription of selenium supplements in these diseases and verify its agreement with current guidelines. Methods: The endocrinologists registered in the Portuguese Medical Association were sent an email with a web-based questionnaire, regarding their knowledge and use of selenium supplements in thyroid autoimmune pathology. Results: A total of 105 physicians (33% of the total) submitted the survey. The selenium serum concentration in the general population was unknown to 80% of respondents. Over a third of respondents have never prescribed selenium for autoimmune thyroid disease. However, 89% are not afraid of recommending it, and 61% indicate Graves' orbitopathy as the pathology they would supplement. In Hashimoto's thyroiditis, 36% of respondents use selenium occasionally or frequently, and this percentage rises to 60% in Graves' disease. Conclusions: Although recommendations only encompass mild Graves' orbitopathy, selenium is prescribed across the spectrum of autoimmune thyroid diseases, probably due to recent studies that consistently show improvement of biochemical hallmarks in these patients. Further investigation is required on the impact of selenium supplements on primarily clinical outcomes and to identify disorders and/or patients who will benefit the most. Also, there is still insufficient knowledge of this field in the medical community, and evidence-based practice should continue to be promoted by endocrinology societies.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear feature: clinical, pathological, and molecular update 5 years after the nomenclature revision.

The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed in 2016 and incorporated as a new entity in the World Health Organization (WHO) classification of tumours of endocrine organs in 2017. Since then, there has been debate regarding the histological criteria for the diagnosis, the need for molecular studies or the risk of lymph node metastasis or recurrence associated with this entity. Over the years, the concept of NIFTP evolved, now including both small (<1 cm) and large (>4 cm) tumours and oncocytic lesions. On the other hand, recent data on NIFTP in the setting of thyroid follicular nodular disease or frequent coexistence of malignant tumours raised concerns regarding the follow-up of these patients. Today, both pathologists and clinicians still face several challenges in the diagnosis, treatment, and follow-up of patients with NIFTP.

The role of ablative treatment in differentiated thyroid cancer management.

INTRODUCTION: The role of ablative treatment in differentiated thyroid cancer management has been evolving over the years. After its introduction in clinical practice, the use of postsurgical radioiodine treatment was generalized to almost every patient with differentiated thyroid cancer, with the exception of unifocal microcarcinomas. However, in the last decade several studies questioned its benefit in low- and intermediate-risk patients. Areas covered: In this review we discuss the role of postsurgical radioiodine treatment at the present time. Expert commentary: Although there is general consensus about the recommendation for very low-risk (microcarcinomas) and high-risk patients - no indication for routine postoperative radioiodine and clear indication for radioiodine treatment, respectively, the recommendation for low- and intermediate-risk patients is still under debate. The most recent guidelines from the American Thyroid Association make a statement against routine postoperative radioiodine in both low- and intermediate-risk cases, recommending an individualized approach that takes into consideration the risk of disease persistence or recurrence after surgery. We consider that these recommendations are in accordance with the best evidence available today, and we would like to emphasize that radioiodine is generally favored for most intermediate-risk patients, especially in the presence of extensive lymph node disease or older age.

TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.

Context: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype. Objectives: To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases. Design and Patients: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue. Results: We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations. Conclusions: When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.

Papillary thyroid microcarcinoma: how to diagnose and manage this epidemic?

The incidence of papillary thyroid microcarcinoma (PTmC) has been increasing everywhere due to the improvement of imaging and morphological diagnoses and probably also due to environmental alterations. Despite this, the mortality caused by thyroid cancer has not increased, reflecting the low clinical aggressiveness of most papillary thyroid carcinomas (PTCs) and the quality of the available treatment. The criteria used to classify PTmC remain questionable, making the clinical risk evaluation of these lesions very difficult. There is no solid basis for establishing the most appropriate tumor size (currently <10 mm) to distinguish PTmC from PTC. Moreover, PTmCs encompass all sorts of PTC histotypes, thus turning the whole group of PTmC genetically and biologically heterogeneous. In this review, we address the 2 most interesting issues from a practical standpoint: Are there any specific morphological or molecular features distinguishing PTmC from PTC? Is it possible to predict the clinical behavior of PTmC in fine needle aspiration biopsy and in surgical specimens, using morphological and/or molecular markers?

Thyroid fine-needle aspiration cytology: is there a place to virtual cytology?

Telecytology has been used for education, training, and consultation. Cytological studies from gynecological, nongynecological and fine-needle aspiration cytology (FNAC) specimens (including studies of thyroid FNAC) analyzed the diagnostic accuracy and reproducibility of telecytology-based predominantly on static digital images. The aim of this study was to evaluate the diagnostic reproducibility of virtual cytology by measuring intraobserver and interobserver agreements among two cytopathologists, using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) nomenclature. 502 glass slides from 222 cases of thyroid FNAC were retrieved and scanned by a high-resolution scanner generating whole slides images (virtual cytology). Conventional and virtual cytology were analyzed by a skilled cytopathologist and the intraobserver agreement rate was 77.5% with the corresponding κ value of 0.54, suggesting a moderate agreement between both methods. A second cytopathologist analyzed the same slides only by virtual cytology and the interobserver agreement rate was 80.2% with the corresponding κ value of 0.57, suggesting a moderate agreement between both cytopathologists. The virtual cytology resulted in a higher proportion of aspirates classified as nondiagnostic (20.3 and 14.9% for the first and second cytopathologist, respectively) as compared to conventional cytology (8.1%). Regarding specific diagnostic categories as defined by the BSRTC nomenclature, the follicular lesion of undetermined significance category presented the lowest concordance rates, corresponding to 5.9% intraobserver agreement and no (0.0%) interobserver agreement. We suggest that virtual cytology can be an alternative to conventional cytology in assessment of thyroid FNAC specimens, but nondiagnostic aspirates obtained by virtual cytology should be reassessed by conventional cytology.