Adriana Gaspar da Rocha

Frequency of TERT promoter mutations in human cancers

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas.

Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.

Stimulated Thyroglobulin at Recombinant Human TSH-Aided Ablation Predicts Disease-free Status One Year Later

CONTEXT Thyroglobulin (Tg) levels measured at the time of remnant ablation after thyroid hormone withdrawal (THW) were shown to have prognostic value in predicting disease-free status. OBJECTIVES Our objectives were to determine whether stimulated Tg levels, measured at the time of remnant ablation performed under recombinant human TSH (rhTSH) stimulation, has value in predicting absence of detectable disease 1 year after radioiodine therapy and to compare the results obtained with this approach with a cohort of patients submitted to ablation after THW. DESIGN This was a prospective observational study. SETTING AND PATIENTS The study included 293 consecutive patients treated for a differentiated thyroid carcinoma with no initial evidence of distant metastasis. All patients were submitted to a total or near-total thyroidectomy, followed by ablation either under rhTSH (n = 151) or endogenous TSH stimulation (n = 142). Patients with positive Tg antibodies were excluded. MAIN OUTCOME MEASURES The predictive value of Tg at ablation was assessed by receiver operating characteristic curve analysis. RESULTS In the rhTSH group, 96 patients (73.3%) were considered disease-free at 1 year. Stimulated Tg at ablation after rhTSH was found to be an independent prognostic indicator of disease persistence 12 months later. The highest-accuracy cutoff value for absence of detectable disease was defined as 7.2 ng/mL, with a negative predictive value of 90%. In the THW group, Tg at ablation also proved to have independent predictive value. Using the same threshold (7.2 ng/mL), the negative predictive value of Tg was 95% in the THW group. CONCLUSIONS When rhTSH was used, stimulated Tg at ablation had independent predictive value for disease-free status 1 year later. A low stimulated Tg at rhTSH-aided ablation may be considered a favorable prognosis factor.

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?

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.

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. Diagn. Cytopathol. 2013;41:793–798.

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 role of ablative treatment in differentiated thyroid cancer management

ABSTRACT 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.