Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

BACKGROUND: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS: [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS: Dexamethasone significantly inhibited T3 uptake at 10 µM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 µM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 µM and 68% at 100 µM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 µM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Features and outcome of differentiated thyroid carcinoma associated with Graves' disease: results of a large, retrospective, multicenter study.

BACKGROUND: Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves' disease (GD) is more aggressive and bound to a less favorable outcome is controversial. OBJECTIVE: Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD-). PATIENTS: Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD-. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. RESULTS: Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD- patients were free of disease. Patients with persistent or recurrent disease (PRD) had "biochemical disease" in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves' orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism. CONCLUSIONS: GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

Genetic interaction analysis of VEGF-A rs3025039 and VEGFR-2 rs2071559 identifies a genetic profile at higher risk to develop nodular goiter.

CONTEXT: Nodular goiter in patients from areas of iodine deficiency is due to the growth of follicular and endothelial cells, involving different vascular-related growth factors in its pathogenesis. OBJECTIVE: The aim of our study was to examine the association of known single polymorphisms of vascular endothelial growth factor-A [VEGF-A], VEGF receptor-2 [VEGFR-2] and hypoxia-inducible factor-1α [HIF-1α] genes or their genetic interactions with the risk of nodular goiter development. PATIENTS AND METHODS: 116 normal subjects, without any thyroid disease, and 108 subjects with nodular goiter [subjects with goiter and at least one thyroid nodule of > 1 cm of maximum size and in absence of signs of autoimmunity] were selected from a homogeneous population living in a mild iodine deficiency geographic area. Analyses were performed on germline DNA obtained from blood samples and VEGF-A rs3025039, VEGFR-2 rs2071559, and HIF-1αrs11549465 SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction [MDR] methodology was applied to investigate the genetic interaction between SNPs. Hardy-Weinberg equilibrium was performed. RESULTS: None of the studied polymorphisms were individually associated with a higher risk to develop nodular goiter [P > 0.05]. The combination of the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms had the highest accuracy of 0.58 [P = 0.018] and the interaction of some genotypes was significantly associated with the risk of nodular goiter development. CONCLUSIONS: Our results support a genetic interaction between the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms as a predictor of the risk to develop nodular goiter in subjects coming from an area with mild iodine deficiency.

Treatment of Graves' hyperthyroidism with thionamides: a position paper on indications and safety in pregnancy.

CONTEXT: Graves' disease affects 3% of women and 0.5% of men in the general population. The first line treatment of Graves' hyperthyroidism is based on the administration of antithyroid drugs (ATD), propylthiouracil (PTU), methimazole (MMI) and carbimazole. A recent warning from the Italian Drug Agency (Agenzia Italiana del Farmaco AIFA) reported the risk of MMI-induced acute pancreatitis. In addition, AIFA highlighted the possible association of MMI treatment during the first trimester of pregnancy with congenital malformations, thus recommending the use of effective contraceptive methods in women of childbearing age treated with MMI. METHODS AND RESULTS: Revision of literature reported less than ten cases of the alleged MMI pancreatitis, allowing the inclusion of MMI in class III drug regarding the relative risk for drug-induced pancreatitis. Data available on the effect of hyperthyroidism per se on the risk of fetal malformations, although scanty, are sufficient to recommend treatment with ATD of the hyperthyroid pregnant woman. Case reports and population studies either suggesting or not suggesting MMI-induced fetal malformations do not allow unquestionable conclusions on this matter. CONCLUSIONS: This consensus by experts from Italian Endocrine and Gynecologic Scientific Societies has edited recommendations derived form the available data and published guidelines of International Scientific Societies.

Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE).

BACKGROUND: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. PURPOSE: We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

Measurement of urinary free cortisol by LC-MS-MS: adoption of a literature reference range and comparison with our current immunometric method.

PURPOSE: One of the best indicators of adrenal gland dysfunction is the level of free cortisol measured in the 24-h urine (UFC) which faithfully reflects the level of biologically active serum cortisol not subjected to circadian variations. Liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) is a sensitive, accurate and precise method recently available in routine laboratories that could remedy interference problems of immunoassays. METHODS: In this study, a literature reference range for UFC measured by LC-MS-MS was verified, and UFC values measured by LC-MS-MS and immunoassay were compared. Immunometric UFC measurement was performed by ACCESS CORTISOL assay without preliminary extraction, using Beckman Coulter UniCel DxI 600 highly automated platform. Liquid chromatography-tandem mass spectrometry UFC measurement was performed by a home-made validated method using cortisol-D4 as internal standard with preliminary deproteinization of urinary samples by centrifugal filter and injection on reverse-phase column. Cortisol was analyzed in positive ion mode with an ESI interface. RESULTS: The reference interval from literature (11-70 µg/day) was confirmed by results obtained for healthy study group. Comparison study of the two methods highlighted a constant and proportional systematic error with a general tendency to overestimate results for the in-use method. CONCLUSIONS: In conclusion, the direct immunometric method overestimates UFC results with respect to liquid chromatography-tandem mass spectrometry which represents the reference method. The literature reference range 11-70 µg/day was confirmed and can be adopted by our lab that will shift all UFC tests performed in routine to the mass spectrometry-based method, satisfying clinicians' request.

The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology.

PURPOSE: Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25-30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. METHODS: Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. RESULTS: The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. CONCLUSIONS: Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology.

Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Graves' disease and Graves' orbitopathy.

BACKGROUND: A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves' orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated. METHODS: We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves' disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups. RESULTS: Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = - 0.376, 95% CI: from - 0.373 to - 0.631; P = 0.005), the significance of which remains to be investigated. CONCLUSIONS: Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.

Thyroid ultrasonography reporting: consensus of Italian Thyroid Association (AIT), Italian Society of Endocrinology (SIE), Italian Society of Ultrasonography in Medicine and Biology (SIUMB) and Ultrasound Chapter of Italian Society of Medical Radiology (SIRM).

Thyroid ultrasonography (US) is the gold standard for thyroid imaging and its widespread use is due to an optimal spatial resolution for superficial anatomic structures, a low cost and the lack of health risks. Thyroid US is a pivotal tool for the diagnosis and follow-up of autoimmune thyroid diseases, for assessing nodule size and echostructure and defining the risk of malignancy in thyroid nodules. The main limitation of US is the poor reproducibility, due to the variable experience of the operators and the different performance and settings of the equipments. Aim of this consensus statement is to standardize the report of thyroid US through the definition of common minimum requirements and a correct terminology. US patterns of autoimmune thyroid diseases are defined. US signs of malignancy in thyroid nodules are classified and scored in each nodule. We also propose a simplified nodule risk stratification, based on the predictive value of each US sign, classified and scored according to the strength of association with malignancy, but also to the estimated reproducibility among different operators.

Relationship between serum cholesterol and Graves' orbitopathy (GO): a confirmatory study.

BACKGROUND: It has been suggested that high cholesterol represents a risk factor for Graves' orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves' disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol. METHODS: The design entailed the inclusion of consecutive patients with a GD of recent onset, with or without GO, who came to our observation to receive radioiodine over a period of 6 months, and a stratification aimed at having two homogeneous group of patients in terms of thyroid function. A total of 86 patients fulfilled the inclusion and evaded the exclusion criteria. All patients underwent an ophthalmological assessment and serum lipids were measured. RESULTS: Serum levels of LDL-cholesterol were significantly higher in patients with GO (135.3 ± 41.3 mg/dL) compared with those without GO (106.6 ± 23.9 mg/dL, P = 0.0007). In a similar manner, serum levels of total cholesterol were higher in patients with GO (211.6 ± 44.0 mg/dL) than in those without GO (176.0 ± 27.2 mg/dL, P = 0.0001). There was no relationship between GO severity and activity and cholesterol. There was no relationship between GO and high-density lipoprotein-cholesterol or triglycerides. CONCLUSIONS: Our study confirms a relationship between the presence of GO and cholesterol in patients with GD of recent onset. Whether lowering of cholesterol ameliorates, GO remains to be established.

Italian consensus on diagnosis and treatment of differentiated thyroid cancer: joint statements of six Italian societies.

BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. METHODS: Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field. OBJECTIVE: The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

mRECIST criteria to assess recurrent thyroid carcinoma treatment response after radiofrequency ablation: a prospective study.

PURPOSE: Surgical removal is recommended for recurrent thyroid carcinomas (RTCs) unable to uptake radioiodine and/or not responsive to chemotherapy. However, repeated neck dissection is difficult for surgeons. Thus, radiofrequency ablation (RFA) was proposed for RTCs. The aim of this prospective study is to assess RTC treatment response after RFA, according to well-established criteria. METHODS: Sixteen lesions in 13 patients were treated by RFA. All patients refused/were excluded from repeated surgery or other conventional therapy. CT and US examinations were performed before RFA to evaluate lesion volume and vascularization. All RFA procedures were performed under US-guidance by an 18-gauge, electrode. Treatment response was evaluated by CT, according to RECIST 1.1 and to mRECIST guidelines; CT examinations were performed during follow-up (6-18 months); the volume of residual vital tumour tissue and the percentage of necrotic tissue were estimated by contrast enhanced CT. RESULTS: RFA was well tolerated by all patients; in two cases laryngeal nerve paralysis was observed. Mean pre-treatment volume was 4.18 ± 3.53 ml. Vital tumour tissue and percentage of necrosis at 6, 12 and 18 months were 0.18 ± 0.25, 0.11 ± 0.13, 0.29 ± 0.40 ml and 91.9 ± 11.1, 90.4 ± 13.3, 80.8 ± 23.1%. According to RECIST 1.1, target lesion response was classified as complete response (CR) in one case, partial response (PR) in 11/16, stable disease in 4/16 cases. According to mRECIST, 11/16 cases were classified as CR and the remaining 5 as PR. CONCLUSION: RFA is a safe procedure to treat the viable tumour tissue and to reduce the RTC volume; as to the criteria to assess treatment response, mRECIST appears to be more accurate.

Rehabilitative orbital decompression for Graves' orbitopathy: results of a randomized clinical trial.

PURPOSE: Orbital decompression (OD) is a consolidated procedure for the treatment of exophthalmos in Graves' orbitopathy (GO). The efficacy of the various procedures remains unclear due to the variability of the techniques used. To address this issue, we performed a randomized clinical trial to compare the efficacy of two surgical techniques. The primary endpoint was the reduction in proptosis. Secondary aims were the risk of post-operative diplopia (POD) in primary gaze and other surgical complications. PATIENTS: 38 patients (76 orbits) affected with GO were enrolled and randomized into single lateral decompression (LD) (n = 19) or balanced medial plus lateral wall decompression (MLD) (n = 19). Following surgery, patients were seen for a follow-up ophthalmological evaluation at 6 months. Pre-operative diplopia in secondary gaze was present in 13/38 patients (34.2%, 8/19 treated with LD and 5/19 treated with MLD). RESULTS: The reduction of exophthalmos was greater in patients treated with MLD (5.1 ± 1.5 mm, range 2-8 mm) than in those treated with LD (3.5 ± 1.3 mm, range 1-6.5 mm) (p = 0.01). The overall incidence of POD in primary gaze was 5/38 (13.2%) and all of these patients had pre-operative diplopia in secondary gaze (5/13, 38.5%, vs patients with no pre-operative diplopia p = 0.005). Two of 19 patients (10.5%) treated with LD and 3/19 (15.8%) treated with MLD, developed POD in primary gaze, with no statistical difference between the two techniques. CONCLUSION: MLD provides a better result in terms of proptosis reduction compared to LD. The two techniques used here appear to have a similar safety profile in terms of POD. Pre-operative diplopia in the secondary gaze remains a major risk factor for development of POD.

Action of three bioavailable antioxidants in orbital fibroblasts from patients with Graves' orbitopathy (GO): a new frontier for GO treatment?

OBJECTIVE: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and an antioxidant approach has been advocated for GO treatment. Here, we investigated the action of three antioxidants in orbital fibroblasts, namely, vitamin C, N-acetyl-L-cysteine, and melatonin. METHODS: Primary cultures of orbital fibroblasts from six GO patients and six control subjects were established. Cells were treated with H2O2 to induce oxidative stress. Cell vitality assays were performed to determine the non-cytotoxic dose of each antioxidant. The following assays were performed: glutathione disulfide (GSSG), as a measure of oxidative stress, cell proliferation, hyaluronic acid (HA), TNFα, IFNγ, and IL1ß. RESULTS: H2O2 induced oxidative stress (augmented GSSG), increased cell proliferation as well as cytokine release, but did not affect HA release. All of the three antioxidant substances reduced H2O2-dependent oxidative stress. Vitamin C reduced proliferation in GO, but not in control fibroblasts. N-acetyl-L-cysteine reduced proliferation and IFNγ in GO, and HA and IL1ß in both GO and control fibroblasts. Melatonin reduced IL1ß and HA in GO and control fibroblasts, and IFNγ only in GO fibroblasts. CONCLUSIONS: Our study provides evidence in support of an antioxidant role of vitamin C, N-acetyl-L-cysteine and melatonin in orbital fibroblasts. Some of the effects of these compounds are exclusive to GO fibroblasts, whereas some other are observed also in control fibroblasts. Our observations provide a basis for a possible clinical use of these substances in patients with GO.

Use of low-dose radioiodine ablation for Graves' orbitopathy: results of a pilot, perspective study in a small series of patients.

OBJECTIVE: Elimination of thyroid antigens by total thyroid ablation (TTA), namely, thyroidectomy followed by radioiodine, may be beneficial for Graves' Orbitopathy (GO). TTA is usually performed with a 131I dose of 30 mCi. In Italy, this dose must be followed by a 24-h protected hospitalization, with increase in the waiting lists. In contrast, a 15 mCi dose can be given without hospitalization and with lower costs. Here, we investigated whether a lower dose of radioiodine can be used to ablate thyroid remnants in patients with GO, after thyroidectomy. METHODS: The study was performed in two small groups of consecutive thyroidectomized patients (six patients per group) with Graves' hyperthyroidism and GO. Patients underwent ablation with either 15 or 30 mCi of 131I following treatment with recombinant human TSH (rhTSH). The primary outcome was rhTSH-stimulated serum thyroglobulin (Tg) at 6 months. The secondary outcome was baseline Tg at 6 months. RESULTS: Baseline Tg and rhTSH-stimulated Tg after at 6 months did not differ between two groups, suggesting a similar extent of ablation. rhTSH-stimulated Tg was reduced significantly compared with rhTSH-stimulated Tg at ablation in both groups. GO outcome following treatment with intravenous glucocorticoids did not differ between the two groups. CONCLUSIONS: Our findings may provide a preliminary basis for the use of a 15 mCi dose of radioiodine upon rhTSH stimulation in thyroidectomized patients with Graves' hyperthyroidism and GO.

Antioxidant effects of ß-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves' orbitopathy (GO).

BACKGROUND: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and several antioxidant agents, namely, selenium, quercetin, enalapril, vitamin C, N-acetyl-L-cysteine, and melatonin, have been shown to reduce oxidative stress and its consequences in primary culture of orbital fibroblasts. In addition, selenium is effective for the treatment of mild GO. Here, we investigated the action of three additional antioxidants in orbital fibroblasts, namely, retinol, ß-carotene, and vitamin E. METHODS: Primary cultures of orbital fibroblasts were established from GO patients and control subjects. To induce oxidative stress, cells were treated with H2O2, after which glutathione disulfide (GSSG) (a parameter of oxidative stress), cell proliferation, hyaluronic acid, TNFα, IFNγ, and IL1ß were measured. RESULTS: H2O2-dependent oxidative stress (augmented GSSG) was associated with increased cell proliferation and cytokine release. All the three antioxidant substances reduced GSSG in both GO and control fibroblasts. ß-carotene reduced proliferation in GO, but not in control fibroblasts. IL1ß was reduced by all three substances. Retinol reduced IFNγ in GO and control fibroblasts. CONCLUSIONS: Our study supports an antioxidant role of retinol, ß-carotene, and vitamin E in orbital fibroblasts from patients with GO and provides a basis for a possible clinical use these substances.

Low frequency of TERT promoter mutations in a series of well-differentiated follicular-patterned thyroid neoplasms.

The diagnostic and clinical approaches to follicular-patterned thyroid neoplasms often create dilemmas for pathologist and clinicians. The molecular analysis of these tumors could be a useful tool to overcome diagnostic limitations. The most frequent molecular alterations are point mutations of RAS family genes. Nevertheless, other molecular markers should be taken into account for their prognostic role, as BRAF mutations and the recently described telomerase reverse transcriptase (TERT) promoter mutation. We investigated the prevalence and the possible role of TERT promoter, BRAF, and RAS mutations in a series of low-risk well-differentiated follicular-patterned thyroid neoplasms. We evaluated 60 follicular adenomas (FA), 29 minimally invasive follicular carcinomas (MIFTC), 82 papillary carcinomas, follicular variant (FVPTC), and 16 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFT-P) for the molecular status of BRAF, H-, N-, K-RAS, and TERT and correlated it with clinic-pathological parameters of tumors. Fifty-seven (30.5%) follicular neoplasms were mutated. In particular, we found 44 RAS mutated neoplasms (23.5%), specifically three FAs, 29 FVPTCs, five NIFT-Ps, and seven FTCs. BRAF mutations were found in ten FVPTCs. Finally, TERT promoter mutations were observed in three FVPTCs and three FTCs; three of them harbored also N-RAS mutations. We confirmed the absence of TERT promoter mutations in benign follicular neoplasms and found a low frequency of TERT promoter mutations in our selected cohort of low-risk follicular-patterned malignancies, speculating their role in the progression and de-differentiation of thyroid cancer.