Search

Aims: Tumour necrosis and/or increased mitoses define high‐grade papillary thyroid carcinoma (PTC). It is unclear whether angioinvasion is prognostic for PTC. Cut‐offs at five or more mitoses/2 mm2 and four or more angioinvasive foci have been empirically defined based upon data from all forms of aggressive non‐anaplastic thyroid carcinomas. Performance of tumour necrosis, mitoses and vascular invasion in predicting distant metastases when specifically applied to PTC is undefined. Methods: We analysed 50 consecutive PTC cases with distant metastases (DM‐PTC): 16 synchronous and 34 metachronous. A total of 108 non‐metastatic PTC (N‐DM‐PTC, 15.0‐year median follow‐up) were used as controls. Invasive encapsulated follicular variant PTC was excluded. Necrosis, mitoses and angioinvasion were quantified. Receiver operating characteristics (ROC) and area under the curve (AUC) analyses determined best sensitivity and specificity cut‐offs predictive of distant metastases. Results: Metastases correlated with necrosis (any extent = 43.8% all DM‐PTC, 53.1% metachronous DM‐PTC versus 5% N‐DM‐PTC; P < 0.001), mitoses (P < 0.001) and angioinvasion (P < 0.001). Mitoses at five or more per 2 mm2 was the best cut‐off correlating with distant metastases: sensitivity/specificity 42.9%/97.2% all DM‐PTC (AUC = 0.78), 18.8%/97.2% synchronous DM‐PTC (AUC = 0.63), 54.6%/97.2% metachronous DM‐PTC (AUC = 0.85). Angioinvasive foci at five or more was the best cut‐off correlating with distant metastases: sensitivity/specificity 36.2%/91.7% all DM‐PTC (AUC = 0.75), 25%/91.7% synchronous DM‐PTC (AUC = 0.79) and 41.9%/91.7% metachronous DM‐PTC (AUC = 0.73). Positive/negative predictive values (PPV/NPV) were: necrosis 22.6%/98.2%; five or more mitoses 32.3%/98.2%; five or more angioinvasive foci 11.8%/97.9%. After multivariable analysis, only necrosis and mitotic activity remained associated with DM‐PTC. Conclusion: Our data strongly support PTC grading, statistically validating World Health Organisation (WHO) criteria to identify poor prognosis PTC. Angioinvasion is not an independent predictor of DM‐PTC. [ABSTRACT FROM AUTHOR]

Objective: Transcriptional activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene were reported at high frequency in aggressive poorly differentiated and anaplastic thyroid cancers. By contrast, the relevance of these mutations in the metastatic behavior of well-differentiated thyroid cancer is still to be defined. The aim of this work was to investigate the frequency of TERT promoter mutations in a remarkable cohort of well-differentiated papillary thyroid carcinoma that developed distant metastases (DM-PTCs) and to establish whether these mutations may be predictive of metastatic behavior. Design: We analyzed the frequency of TERT promoter mutations in a group of 43 highly aggressive DM-PTCs. As controls, we analyzed these mutations in a group of 78 PTCs without distant metastases (control-PTCs). The possible correlation between TERT promoter mutations and BRAF V600E mutation was also investigated. Methods: TERT promoter mutational status was evaluated by direct sequencing of the hotspot harboring the C228T and the C250T mutations. Results: In the overall cohort of 121 PTCs analyzed, 17% of cases (21/121) carried a mutation in the TERT promoter. Noticeably, 33% of DM-PTCs were mutated in the TERT promoter while only 9% of the control-PTCs showed a mutation in this locus. We also observed a positive association between BRAF V600E and TERT C228T mutations in the cohort of DM-PTCs. Conclusions: These results indicate that TERT promoter mutations are associated with the development of distant metastases in PTCs and may help in predicting aggressive behavior in this type of tumor. [ABSTRACT FROM AUTHOR]

Background: The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated 68Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. Methods: We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19-78 years). In all patients, [18F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and 68Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with 111In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq 90Y-DOTATOC/administration. Serial 68Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by 68Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. Results: 68Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by 68Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT ( p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. Conclusions: In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. 68Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role. [ABSTRACT FROM AUTHOR]

The agreement of the different cytological categories used worldwide is a long lasting and highly debated topic. Although the systems are broadly similar, some differences still exist especially in grey areas, i.e. the poorly defined classes like Thy3a. Trying to reduce the interobserver variability, we limit the diagnosis of THY3a to cases with scanty atypia (SA), which is the first and most important pattern described by Van der Horst et al. and encompasses cases in which some atypical features are present but their interpretation can be influenced by cell scarcity, artefacts and cystic changes. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to report the rationale and selectio n criteria for hemithyroidectomy and ipsilateral central neck dissection in patients with selected papillary thy roid cancer and to report the surgical and oncological outcomes. Design: Single-institution retrospective observational study. Methods: The clinical records of patients with a histopathological diag nosis of low-risk pT1 papillary thyroid cancer who underwent hemithyroidectomy with or without ipsilateral central neck dissection between March 2000 and April 2018 at a tertiary referral center were retrospectively reviewed. De mographic, clinical, and histopathological data were collected. Results: During the study period, 176 patients underwent hemithyroidect omy for PTC. Thirteen patients (13/176, 7.39%) were lost to follow-up and 74 patients (74/163 45.40%) underwen t completion thyroidectomy within 1 month because they were classified intermediate ATA initial risk based on defin itive pathology. The final study group was composed of 89 patients, who had a median follow-up of 5.3 years. The me an follow-up was 6.3 years (range: 36-207 months). Eighty-four patients (94.38%) did not experience recurrence in the follow-up period. A total of 5/89 patients (5.62%) underwent delayed completion thyroidectomy with or without neck dissection for recurrent malignancy in the residual lobe (3/5) or regional lymph nodes (2/5). The median time from surgery to recurrence was 24.8 months (range: 6-60). The follicular variant was an independent risk factor for recur rence. Conclusions: Hemithyroidectomy with or without prophylactic ipsilateral cen tral neck dissection is a valuable treatment option in selected low-risk papillary thyroid cancers and ensur es a low risk of recurrence. Prophylactic ipsilateral central compartment dissection could have a role in improving c ancer staging, and accurate ultrasonographic follow-up is essential to identify local recurrence. [ABSTRACT FROM AUTHOR]

Combined application of ultrasound and SPECT/CT has incremental value in detecting parathyroid tissue in SHPT patients. A, inferior thyroid artery; c, common carotid artery; p, parathyroid adenoma; t, thyroid lobe; inf, inferior; sup, superior gl Intraoperative parathyroid hormone testing testing Venous blood sampling was taken three times: before incision (basal level), after manipulation of the adenoma and 7 minutes after its complete excision. Reduced surgical manipulation in a cohort of patients treated by minimally invasive parathyroidectomy with ultrasonography-based visual map The correct localisation of parathyroid adenomas is one of the main difficulties during mini-invasive parathyroidectomy. [Extracted from the article]

Objective: Thyroid surgery may lead to postoperative complications. The a im of this paper was to determine whether the rate of postoperative hypoparathyroidism (HPT) is influenced by whether surgery is staged. Design: Single-institution retrospective observational study. Methods: The clinical records of 786 patients treated at the Otolaryngo logy Unit of the Azienda USL-IRCCS di Reggio Emilia between January 1990 and December 2015 were reviewed. Pa tients were divided into two groups according to the surgical treatment received: group TT (637 patients, 81.04%) underwent single-stage total thyroidectomy; Group cT (149 patients, 18.96%) underwent loboisthmusectomy and delay ed completion total thyroidectomy. Transient and permanent HPT, assessed after 6 months of follow-up, were the p rimary endpoints. Risk factors of postoperative HPT were also analysed as secondary outcomes. Results: Rates of transient HPT in group TT were higher than those obse rved in group cT, (P = 0.0057). Analysis of risk factors identified sex as an independent risk factor for transie nt HPT only for group TT (P = 0.0012) and the number of parathyroid glands remaining in situ (PGRIS) as an independent risk factor for transient and perman ent HPT for group TT (P < 0.0001 and P = 0.0002, respectively). Conclusions: This study suggests that the risk of transient postoperative H PT is lower in patients that undergo completion thyroidectomy. Further independent risk factors for postoperative HPT are female sex and PGRIS score. In light of the growing use of conservative surgery for thyroid ne oplasms, these findings could help to adequately plan surgery in order to reduce endocrine complications. [ABSTRACT FROM AUTHOR]

During pregnancy, thyroid homeostasis is physiologically modified, leading to altered levels of thyrotropin (TSH): hence, the adoption of pregnancy-related, population- and method-specific reference ranges is recommended. This monocentric and retrospective study was conducted to establish local pregnancy-related reference intervals for serum TSH in singleton pregnant women using real-life clinical data. We included women who measured serum TSH during pregnancy at our Laboratory over six years, excluding pregnant women with current or past history of thyroid disease, pituitary or autoimmune diseases, use of medications known to influence thyroid function, multiple and/or pathological pregnancies, BMI >30 Kg/m2. We retrieved a total of 3744 TSH results. Reference limits (90% confidence intervals) for TSH (in mIU/L) are: first trimester 0.09 (0.06–0.12) − 3.16 (3.05–3.29); second trimester 0.25 (0.11–0.30) − 3.55 (3.34–3.73); third trimester 0.42 (0.15–0.48) − 3.93 (3.80–4.08). In conclusion, real-life clinical data could be used to establish or verify local reference intervals for TSH in pregnant women: this may reduce the risk of misclassification of pregnant women undergoing thyroid function testing. [ABSTRACT FROM AUTHOR]

Background: Single-center trials demonstrated moderate-substantial level of interobserver agreement in the evaluation of ultrasound (US) features of thyroid nodules. Multicenter studies on US agreement, however, are scanty, and data on intraobserver agreement are poor. Aim of the study was to assess inter- and intraobserver agreement between different thyroid centers and different specialists. Methods: A blinded analysis of 100 electronically recorded thyroid nodule US images was conducted in three large-volume thyroid centers by seven radiologists and endocrinologists. The evaluation was repeated after randomization 4 months later. The following US characteristics were evaluated: composition, echogenicity, margins, intranodular echogenic spots, vascularity, and shape. Thyroid nodules were also classified according to AACE/ACE/AME, EU-TIRADS, ATA, and ACR-TIRADS US classifications. Intra- and interobserver agreement was calculated using cross-tabulation expressed as mean Cohen's Kappa. Results: Interobserver agreement for US features: K-coefficient was 0.53 for composition, 0.47 for echogenicity, 0.46 for intranodular vascularity, and 0.33 for margins of the nodules. For echogenic foci, the K-coefficient was 0.47 for microcalcifications, 0.38 for macrocalcifications, 0.11 for the subcategory comet-tail artifacts, and 0.42 for shape. Operators resulted uncertain on hyperechoic foci definition in 16% of cases and described them as "hyperechoic foci of uncertain significance." Interobserver Cohen-K for US classification systems was 0.44 for AACE, 0.42 for ACR-TIRADS, 0.39 EU-TIRADS, and 0.34 for ATA. Intraobserver agreement: the K-coefficient for nodule US features was 0.62 for intranodular vascularity, 0.58 for composition, 0.60 for echogenicity, 0.54 for macrocalcifications, 0.55 for microcalcifications, 0.47 for comet tails, 0.39 for margins, and 0.35 for shape. Intraobserver Cohen-K for US classification systems was 0.54 for AACE, 0.49 for ACR-TIRADS, 0.38 for ATA, and 0.33 for EU-TIRADS. Conclusions: Intraobserver reproducibility for thyroid nodule US reporting and US classification systems appears fairly adequate, while the interobserver agreement between different centers is lower than that assessed in single-center trials. Reporting and rating ability of thyroid US examiners still appear not consistent. An unified lexicon of thyroid US features, a simplified method of classification, and a dedicated training in the description of thyroid US findings may increase the observers' agreement and the predictive value of US classification systems in real world practice. [ABSTRACT FROM AUTHOR]

Background: Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs. Methods: A total of 431 mPTCs cases were collected from six Italian institutions, and TERT promoter mutational status was assessed by a next-generation sequencing approach. Results: TERT promoter mutations were found in 4.7% of the analyzed mPTCs, showing that even microcarcinomas carry mutations in this gene. Correlation analysis showed that TERT promoter mutations are not associated with aggressive features or clinical outcome in the cohort analyzed. Conclusions: TERT mutations are present but uncommon in mPTCs. Apparently, in mPTCs, the occurrence of TERT mutations is not correlated with unfavorable clinical features. [ABSTRACT FROM AUTHOR]

Objective To report the Italian experience on cinacalcet use following its approval by the European Medical Agency ( EMA) to control hypercalcaemia in patients with primary hyperparathyroidism ( PHPT). Design Retrospective data collection from 100 patients with sporadic (s PHPT) and 35 with familial PHPT (f PHPT) followed in eight Italian centres between October 2008 and March 2011. Measurements Albumin-adjusted serum calcium, PTH, 25 OHD, daily cinacalcet dose and adverse events were recorded during the follow-up (1-46 months). Results Baseline serum calcium was 2·90 ± 0·27 nmol/l in s PHPT and 2·75 ± 0·17 nmol/l in f PHPT patients ( P = 0·007). The cinacalcet EMA labelling was met in 53% s PHPT and 26% f PHPT patients. High surgical risk (34%), negative preoperative imaging (19%), control of hypercalcaemia before parathyroidectomy ( PTx) (24%), and refusal of PTx (19%) accounted for cinacalcet prescription in 96% of s PHPT patients. Conversely, initial treatment (34%), persistent/relapsing PHPT after surgery (31%), and refusal of PTx (14%) were the indications in 79% f PHPT patients. Cinacalcet was started at 30 mg/daily in 64% of s PHPT and 91% of f PHPT and increased until normocalcaemia was reached or side effects occurred. The final daily dose ranged between 15 and 120 mg. The majority of patients (65% of s PHPT and 80% of f PHPT) become normocalcaemic. Treatment was withdrawn in six patients because of side effects. Conclusions There is a wide heterogeneity in the prescription of cinacalcet in PHPT patients in Italy and the EMA labelling is not always followed, particularly in f PHPT patients. Cinacalcet effectively reduces serum calcium in patients with either s PHPT or f PHPT. [ABSTRACT FROM AUTHOR]

OBJECTIVE Insulin-like growth factor binding-protein-1 (IGFBP-1) has a role in glucose homeostasis and is present at high concentrations in hyperthyroidism. We have investigated the relationship between IGFBP-1 concentration and glucose homeostasis in hyperthyroidism. DESIGN Patients and controls had intravenous glucose tolerance tests (IVGTT) and/or oral glucose tolerance tests (OGTT). Patients were tested when hyperthyroid and when euthyroid whilst the controls were tested once. The IVGTT was used to assess insulin sensitivity and the OGTT to establish that the study group had abnormal glucose tolerance. The hyperthyroid patients were treated with methimazole to restore euthyroidism. PATIENTS Ten patients (9 females) and 13 healthy controls (9 females) consented to the study. Ten patients and nine controls (7 females) had IVGTT. Six patients (5 females) and six controls (4 females) had OGTT. MEASUREMENTS Glucose, insulin, glucagon, GH and IGFBP-1 were measured during GTT. IGF-I, free thyroid hormones, and TSH concentrations were measured basally. RESULTS Hyperthyroid subjects were insulin resistant and 67% had impaired glucose tolerance. Fasting IGFBP-1 levels were doubled in hyperthyroid subjects compared to healthy controls and correlated positively with free T4 (r = 0.84, P < 0.0001), with peak glucose during the OGTT (r = 0.68, P < 0.005) with peak insulin during the IVGTT (r = 0.51, P < 0.005) and negatively with glucose disappearance constant (r = - 0.52, P < 0.005). IGFBP-1 was highly phosphorylated in hyperthyroid and control subjects. Fasting insulin and IGFBP-1 levels were unrelated but IGFBP-1 suppressed acutely during GTT in all groups. GH levels fell less in patients with hyperthyroidism than in normals during GTTs. CONCLUSIONS We conclude that in hyperthyroidism thyroid hormones directly increase fasting IGFBP-1 concentration but acute regulation of IGFBP-1 by insulin is normal and that elevated fasting phosphorylated IGFBP-1 concentration is... [ABSTRACT FROM AUTHOR]