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Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology(AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence and only those classified as “critical” were considered in the formulation of recommendations. Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

BackgroundThe detection of thyroid nodules has been increasing over time, resulting in an extensive use of fine-needle aspiration (FNA) and cytology. Tailored methods are required to improve the management of thyroid nodules, including algorithms and web-based tools.Study aimsTo assess the performance of the Thyroid Nodule App (TNAPP), a web-based, readily modifiable, interactive algorithmic tool, in improving the management of thyroid nodules.MethodsOne hundred twelve consecutive patients with 188 thyroid nodules who underwent FNA from January to December 2016 and thyroid surgery were retrospectively evaluated. Neck ultrasound images were collected from a thyroid nodule registry and re-examined to extract data to run TNAPP. Each nodule was evaluated for ultrasonographic risk and suitability for FNA. The sensitivity, specificity, positive and negative predictive values, and overall accuracy of TNAPP were calculated and compared to the diagnostic performance of the other two algorithms by the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME), which it was derived from the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS).ResultsTNAPP performed better in terms of sensitivity (>80%) and negative predictive value (68%) with an overall accuracy of 50.5%, which was similar to that found with the AACE/ACE/AME algorithm. TNAPP displayed a slightly better performance than AACE/ACE/AME and ACR TI-RADS algorithms in selectively discriminating unnecessary FNA for nodules with benign cytology (TIR 2 - Bethesda class II: TNAPP 32% vs. AACE/ACE/AME 31% vs. ACR TI-RADS 29%). The TNAPP reduced the number of missed diagnoses of thyroid nodules with suspicious and highly suspicious cytology (TIR 4 + TIR 5 - Bethesda classes V + VI: TNAPP 18% vs. AACE/ACE/AME 26% vs. ACR TI-RADS 20.5%). A total of 14 nodules that would not have been aspirated were malignant, 13 of which were microcarcinomas (92.8%).DiscussionThe TNAPP algorithm is a reliable, easy-to-learn tool that can be readily employed to improve the selection of thyroid nodules requiring cytological characterization. The rate of malignant nodules missed because of inaccurate characterization at baseline by TNAPP was lower compared to the other two algorithms and, in almost all the cases, the tumors were microcarcinomas. TNAPP’s use of size >20 mm as an independent determinant for considering or recommending FNA reduced its specificity.ConclusionTNAPP performs well compared to AACE/ACE/AME and ACR-TIRADS algorithms. Additional retrospective and, ultimately, prospective studies are needed to confirm and guide the development of future iterations that incorporate different risk stratification systems and targets for diagnosing malignancy while reducing unnecessary FNA procedures.

Objective Thyroid nodule ultrasound characteristics are used as an indication for fine-needle aspiration cytology, usually as the basis for Thyroid Imaging Reporting and Data System (TIRADS) score calculation. Few studies on interobserver variation are available, all of which are based on analysis of preselected still ultrasound images and often lack surgical confirmation. Methods After the blinded online evaluation of video recordings of the ultrasound examinations of 47 consecutive malignant and 76 consecutive benign thyroid lesions, 7 experts from 7 thyroid centers answered 17 TIRADS-related questions. Surgical histology was the reference standard. Interobserver variations of each ultrasound characteristic were compared using Gwet’s AC1 inter-rater coefficients; higher values mean better concordance, the maximum being 1.0. Results On a scale from 0.0 to 1.0, the Gwet’s AC1 values were 0.34, 0.53, 0.72, and 0.79 for the four most important features in decision-making, i.e. irregular margins, microcalcifications, echogenicity, and extrathyroidal extension, respectively. The concordance in the discrimination between mildly/moderately and very hypoechogenic nodules was 0.17. The smaller the nodule size the better the agreement in echogenicity, and the larger the nodule size the better the agreement on the presence of microcalcifications. Extrathyroidal extension was correctly identified in just 45.8% of the cases. Conclusions Examination of video recordings, closely simulating the real-world situation, revealed substantial interobserver variation in the interpretation of each of the four most important ultrasound characteristics. In view of the importance for the management of thyroid nodules, unambiguous and widely accepted definitions of each nodule characteristic are warranted, although it remains to be investigated whether this diminishes observer variation.

Objective Thyroid surgery may lead to postoperative complications. The aim 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 Otolaryngology Unit of the Azienda USL-IRCCS di Reggio Emilia between January 1990 and December 2015 were reviewed. Patients 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 delayed completion total thyroidectomy. Transient and permanent HPT, assessed after 6 months of follow-up, were the primary endpoints. Risk factors of postoperative HPT were also analysed as secondary outcomes. Results Rates of transient HPT in group TT were higher than those observed in group cT, (P = 0.0057). Analysis of risk factors identified sex as an independent risk factor for transient 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 permanent HPT for group TT (P < 0.0001 and P = 0.0002, respectively). Conclusions This study suggests that the risk of transient postoperative HPT 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 neoplasms, these findings could help to adequately plan surgery in order to reduce endocrine complications.

Background: Thyroid nodule image reporting and data systems (TIRADS) provide the indications for fine-needle aspiration (FNA) based on a combination of nodule sonographic features and size. We compared the TIRADS-based recommendations for FNA with those based on the personal expertise of qualified US investigators in the diagnosis of thyroid malignancy. Methods: Seven highly experienced ultrasound (US) investigators from 4 countries evaluated, online, the US video recordings of 123 histologically verified thyroid nodules. Technical resources provided the operators with a diagnostic approach close to the real-world practice. Altogether, 4,305 TIRADS scores were computed. The combined diagnostic potential of TIRADS (TIRSYS) and the personal recommendations of the investigators (PERS) were compared against 3 possible goals: to recognize all malignant lesions (allCA), nonpapillary plus non-pT1 papillary cancers (nPnT1PCA), or stage II-IV cancers (st2-4CA). Results: For allCA and nPnT1PCA, TIRSYS had lower sensitivity than PERS (69.8 vs. 87.2 and 83.5 vs. 92.6%, respectively, p <0.01), while in st2-4CA the sensitivities were the same (99.1 vs. 98.6% and TIRSYS vs. PERS, respectively). TIRSYS had a higher specificity than PERS in all 3 types of cancers (p < 0.001). PERS recommended FNA in a similar proportion of lesions smaller or larger than 1 cm (76.9 vs. 82.7%; ns). Conclusions: Recommendations for FNA based on the investigators’ US expertise demonstrated a better sensitivity for thyroid cancer in the 2 best prognostic groups, while TIRADS methodology showed superior specificity over the full prognostic range of cancers. Thus, personal experience provided more accurate diagnoses of malignancy, missing a lower number of small thyroid cancers, but the TIRADS approach resulted in a similar accuracy for the diagnosis of potentially aggressive lesions while sparing a relevant number of FNAs. Until it is not clearly stated what the goal of the US evaluation is, that is to diagnose all or only clinically relevant thyroid cancers, it cannot be determined whether one diagnostic approach is superior to the other for recommending FNA.

Classification schemes for reporting thyroid cytology of fine needle aspiration (FNA) of thyroid nodules are largely used in clinical practice, but the level of inter-observer agreement among cytopathologists is poorly acknowledged. The present study aimed to explore the inter-observer agreement among the experienced authors of the 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC). A stratified randomization was performed in order to obtain a sample homogeneously distributed and representative of all ICCRTC classes. Four high-experience raters were randomly selected among the extensors of the Italian consensus. They independently reviewed 60 FNA samples blindly of the initial cytological report and clinical features. Their overall agreement was evaluated according to Fleiss' kappa. The overall inter-observer agreement was moderate (κ 0.46). Specifically, a good agreement was found when the samples were consistent for malignancy (TIR5) or were not adequate for diagnosis (TIR1) (κ 0.67 and κ 0.73, respectively). A moderate agreement was present for suspicious-for-malignant category (TIR4), and a fair agreement was recorded in the two intermediate ones (TIR3A and TIR3B) (κ 0.36 and κ 0.35, respectively). For clinical purposes, the agreement was good (κ 0.74) in differentiating cases with surgical indication (TIR4/TIR5) from those in which surgery is not essential or requires limited extension (TIR3B/TIR3A/TIR2). In conclusion, the present study confirms the reliability of ICCRTC. These data represent a reference for cytopathologists using this system and are useful for the practice of clinicians and surgeons.

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, BMI30 Kg/mWe 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.

Objective: Image-guided interventional ultrasound (US) techniques represent diagnostic and therapeutic tools for non-surgical management of thyroid nodular disease. We sought to investigate the attitude of European Thyroid Association (ETA) members towards the use of minimally invasive techniques (MIT) in diagnosis/therapy of symptomatic nodular goitre. Methods: ETA members were invited to participate in an online survey investigating the use of MIT in benign and malignant thyroid nodular disease. Of 865 invited members, 221 (25.5%) completed the survey. The respondents were from 40 countries; 139 (74.7%) were from European countries. Results: Respondents personally performed thyroid US (91.6%), Fine needle aspiration (FNA; 75.3%), ethanol ablation (EA; 22.1%), core needle biopsy (CNB; 11%) and thermal treatments (4.8%). When skills and/or technology were unavailable, only 13.4% referred patients “often” or “always” to other centres with specific expertise in this field. Surgery was the preferred first option in patients with recurrent cysts, 4.0 cm benign nodules, local (radioiodine-avid or non-avid) lymph node metastases, or papillary cancers

Standard therapeutic approaches for benign thyroid lesions that warrant intervention are surgery for cold and either surgery or radioiodine for autonomously functioning thyroid nodules (AFTN). Image-guided thermal ablation (TA) procedures are increasingly proposed as therapy options for selected clinical conditions. Due to mounting scientific evidence and widening availability, ETA considered it appropriate to develop guidelines for the use of TA in adult patients. TA procedures are well tolerated, but a dedicated training of the operators is required and information on possible complications needs to be shared with the patients. The following factors should be considered when weighing between observation, surgery, and TA for benign thyroid nodules. In solid non-hyperfunctioning nodules, TA induces a decrease in thyroid nodule volume, paralleled by improvement in symptoms. Nodule re-growth is possible over time and may necessitate repeat treatment, or surgery, in a dialogue with the patient. In AFTN, radioactive iodine is the first-line treatment, but TA may be considered in young patients with small AFTN due to higher probability of restoring normal thyroid function and avoidance of irradiation. In cystic nodules, ethanol ablation (EA) is the most effective and least expensive treatment. TA may be considered for cystic lesions that relapse after EA or have a significant residual solid component following drainage and EA. TA should be restricted to benign lesions that cause symptoms or cosmetic concern. Presently, laser and radiofrequency ablation are the most thoroughly assessed techniques, with similar satisfactory clinical results. Microwaves and high-intensity focused ultrasound therapy options remain to be fully evaluated.

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.

Objective The aim of this study was to report the rationale and selection criteria for hemithyroidectomy and ipsilateral central neck dissection in patients with selected papillary thyroid cancer and to report the surgical and oncological outcomes. Design Single-institution retrospective observational study. Methods The clinical records of patients with a histopathological diagnosis 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. Demographic, clinical, and histopathological data were collected. Results During the study period, 176 patients underwent hemithyroidectomy for PTC. Thirteen patients (13/176, 7.39%) were lost to follow-up and 74 patients (74/163 45.40%) underwent completion thyroidectomy within 1 month because they were classified intermediate ATA initial risk based on definitive pathology. The final study group was composed of 89 patients, who had a median follow-up of 5.3 years. The mean 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 recurrence. Conclusions Hemithyroidectomy with or without prophylactic ipsilateral central neck dissection is a valuable treatment option in selected low-risk papillary thyroid cancers and ensures a low risk of recurrence. Prophylactic ipsilateral central compartment dissection could have a role in improving cancer staging, and accurate ultrasonographic follow-up is essential to identify local recurrence.

Background: Until recently, treatment of hypothyroidism has been accomplished using monotherapy of synthetic L-thyroxine (L-T4) sodium tablets that should be taken 30-60 minutes before breakfast. Nowadays, a liquid preparation of levothyroxine is available and can effectively replace tablets without the need of waiting before having breakfast. Evidence of Quality of life (QoL) improvement when shifting from the former to the latter preparation, however, is still lacking. Objective: The study aimed to assess changes in QoL of hypothyroid patients dissatisfied with their therapy with L-T4 sodium tablets who were switched from tablets taken 30-60 minutes before breakfast to liquid L-T4 at breakfast. Methods: A total of 418 consecutive hypothyroid subjects treated by means of L-T4 tablets were asked about their satisfaction/dissatisfaction in order to take the medication 30-60 minutes before having breakfast. Overall, 110 patients (26.3%) complained of the timing of their L-T4 therapy (30-60 minutes before breakfast). A dedicated QoL questionnaire (ThyTSQ), taking just a few minutes to be filled in was then administered to these dissatisfied patients. They were therefore switched to L-T4 to be taken at breakfast. Aiming to avoid TSH elevation due to L-T4 tablets malabsorption caused by meal interference and gastric pH changes, patients were invited to take L-T4 liquid form, as this is claimed to be scarcely affected by the non-fasting state. The questionnaire (ThyTSQ) was administered again at the control visit 3 months later. TSH, FT4, FT3 serum concentrations and metabolic parameters were also recorded. Results: An improved QoL, mainly due to an easier adherence to treatment, was reported by 66.6% of 102 patients who completed the study after shifting from taking medication 30-60 minutes before breakfast to at breakfast ingestion (P 2mIU/L Conclusion: In hypothyroid subjects dissatisfied with L-T4 tablets ingested 30-60 minutes before breakfast, the shift to the same dose of L-T4 in liquid form taken at breakfast improved QoL in the majority of patients, without affecting thyroid function.

Background: Single-center trials have demonstrated an acceptable level of inter-observer agreement in the evaluation of the ultrasound (US) features of thyroid nodules, but limited data are available about the consistency in the assessment of US findings among different thyroid centers. Aim of the study: to assess the inter-observer agreement between different thyroid centers and among different specialists in the evaluation of the main US features of thyroid nodules. Materials and methods A blinded retrospective analysis of 100 electronically-recorded US images was conducted in three large-volume thyroid centers by seven qualified thyroid imaging experts, two radiologist and five endocrinologists. The following US features were evaluated: composition (solid, predominantly solid, predominantly cystic, and cystic); echogenicity (hyperechoic, isoechoic, mildly and deeply hypoechoic); margins (well-defined, ill-defined, microlobulated, and spiculated); calcifications (absent, microscopic, macroscopic, eggshell); hyperechoic foci of uncertain significance; comet-tail artifacts; vascularity (no vascular signals, perinodular and/or slight intranodular flow, and marked intranodular flow). Thyroid nodules were also classified according to four major US classification systems: AACE/ACE/AME, EU-TIRADS, ATA and ACR. The inter-observer agreement was calculated using cross-tabulation expressed in Cohen's Kappa. Kappa values were evaluated, according to Landis and Koch, as follows: 0-0.20 poor, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.80 substantial, and 0.81-1.0 almost perfect agreement. A sub-analysis assessed how many times and how many operators evaluated as suspicious for malignancy the US features of each nodule. Results: The inter-observer agreement resulted in a K-correlation coefficient of 34.5%, 44.0%, 42.3% and 38.8% for the ATA, AACE/ACE/AME, ACR, and EU-TIRADS classification systems, respectively. The interobserver agreement for the main thyroid nodule US findings resulted as follows: composition 53.2%; echogenicity 46.9%; margins 33.2%; comet-tail 10.6%, microcalcifications 46.8%; macrocalcifications 37.7%; eggshell calcifications 64.9%; intranodular vascularity 45.9%. Conclusion: The level of agreement among different thyroid centers in the description of suspicious US features in thyroid nodules ranged from fair to moderate, with the lowest level of consistency for the characteristics of margins and the presence of comet-tails. A similar range of variability was demonstrated also for the four US classification systems. An universally accepted lexicon of thyroid US features and a dedicated training in thyroid US findings definition are needed to improve the inter-observer agreement and the predictive value of US classification systems in real world practice.

Background: While thyroid nodules are frequent in endocrine clinical practice, patients are often asymptomatic and euthyroid, and death is rare in cases of malignancy. Objectives: To evaluate the perception of current international guidelines regarding thyroid nodule management among Italian endocrinologists, and to compare daily clinical practice with suggested recommendations. Methods: Italian Association of Clinical Endocrinologists (AME) members were invited to participate in a Web-based survey. Results: A total of 566 physicians responded. About 50% had read the full text of the guidelines. Over half appreciated the suggested ultrasound (US) risk categories. Fine-needle aspiration (FNA) was obtained more frequently than recommended. Follow-up of a cytologically benign nodule was largely performed according to the guidelines. Molecular testing would be most commonly requested when cytology reports showed atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (TIR3A for Italian System). Iodine and/or levothyroxine were largely prescribed for cytologically benign asymptomatic nodules. Laser/radiofrequency ablation and percutaneous ethanol injection were commonly considered as alternatives to surgery (46.2 and 71.4%, respectively). Conclusions: Efforts are needed to make the guidelines more user-friendly and to encourage the use of codified risk categories in thyroid US reports. FNA indications remain a matter of debate as FNA is obtained in clinical practice more often than is recommended. Current US follow-up modalities for a benign nodule are correct, but probably could be performed less frequently without any harm. Molecular testing, if accessible, would be helpful in guiding clinicians' strategies in cases of AUS/FLUS-TIR3A cytologic results. Nonsurgical procedures are favorably embraced.

Due to its wide accessibility, easiness of use, and inexpensive cost, ultrasound (US) examination of the thyroid gland and cervical lymph nodes is commonly employed for the diagnosis of diffuse and nodular thyroid disease and for the pre-operatory staging and follow-up of patients with thyroid malignancy.

In the last two decades Peptide Receptor Radionuclide Therapy (PRRT) has acquired great importance as an alternative or complementary tool in the treatment of neuroendocrine tumors (NETs) and other somatostatin receptor (SSTR) positive tumors. Many experiences of PRRT using different radiopharmaceuticals, mainly beta-emitters 90Yttrium (90Y) and 177Lutetium (177Lu) labeled peptides, are reported in the literature with encouraging results in terms of tumor regression, self-assessed quality of life, and overall survival. SSTRs are mainly expressed in Gastro-Entero-Pancreatic neuroendocrine tumors (GEP-NETs) but in many other neoplasms (NETs and non-NETs) it is possible to find a high SSTR expression. Some of these are pheochromocytoma/paraganglioma, bronchial NET, thymic NET, meningioma, thyroid cancer (differentiated and medullary) and Merkel cell carcinoma.

Well-established criteria for evaluating the response to treatment and the appropriate followup of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

Objectives/Hypothesis The aim of this study was to identify any possible predictive factors of lateral neck recurrence in patients with papillary thyroid carcinoma with no ultrasonographic and/or cytological evidence of lymph node metastasis at time of diagnosis. The influence of lateral neck recurrence on survival was also investigated. Study Design Observational retrospective study. Methods Retrospective review of clinical records of 610 patients surgically treated for papillary thyroid carcinoma with clinically negative lymph nodes at the Otolaryngology Unit of the Arcispedale Santa Maria Nuova–IRCCS, Reggio Emilia, Italy, from January 1984 to December 2008. Results Lateral neck recurrences were ipsilateral to the primary tumor in all cases and were associated with the occurrence of more aggressive histological variants and central neck metastasis. Lateral neck recurrences were more frequently observed in patients with distant metastases and were associated with a reduced disease-specific survival. Conclusion Lateral neck compartment ipsilateral to the tumor was the most common site of recurrence, with about half of cases appearing in the first 28 months of follow-up. In patients with papillary thyroid carcinoma, detection of lateral neck metastases prior to first surgery is crucial to surgical planning. Aggressive histological variants and postsurgical evidence of lymph node metastasis from papillary thyroid carcinoma in central neck compartment are associated with a higher risk of lateral neck recurrence. In these patients, a closer postsurgical ultrasound surveillance of the lateral neck compartments seems worthwhile. Level of Evidence 4. Laryngoscope, 125:2226–2231, 2015

Somatostatin (SST) is a 28-amino-acid cyclic neuropeptide mainly secreted by neurons and endocrine cells. A major interest for SST receptors (SSTR) as target for in vivo diagnostic and therapeutic purposes was born since a series of stable synthetic SST-analouges PET became available, being the native somatostatin non feasible for clinical use due to the very low metabolic stability. The rationale for the employment of SST-analogues to image cancer is both based on the expression of SSTR by tumor and on the high affinity of these compounds for SSTR. The primary indication of SST-analogues imaging is for neuroendocrine tumors (NETs), which usually express a high density of SSTR, so they can be effectively targeted and visualized with radiolabeled SST-analogues in vivo. Particularly, SST-analogues imaging has been widely employed in gastroenteropancreatic (GEP) NETs. Nevertheless, a variety of tumors other than NETs expresses SSTR thus SST-analogues imaging can also be used in these tumors, particularly if treatment with radiolabeled therapeutic SST-analouges PET is being considered. The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with68Ga-radiolabeled SST-analouges PET in tumors other than GEP-NETs.

The relevance of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) as a negative prognostic factor is a subject of intense debate. This mutation has been associated with several clinicopathological features, but the lack of consistency among data does not support its usefulness as marker of tumor aggressiveness and poorer outcome. Due to the genetic heterogeneity of the tumor, both the occurrence and the allele percentage of the BRAF mutation should be considered to unravel this controversy.We aimed to evaluate the impact of the BRAF V600E mutation occurrence and the allele percentage on the metastatic process in PTCs.The presence and allele percentage of the BRAF mutation were determined by pyrosequencing in 132 cases of well-differentiated PTCs with (n = 37) or without lymph node metastases (LNMs) (n = 95) and in 40 LNMs matched with 35 PTCs.No significant differences were observed in either the occurrence or the allele percentage of V600E mutation between the 2 groups of PTCs with or without LNMs. The LNMs were heterogeneous for the V600E mutation as the primary lesions.In this study, the occurrence and percentage of the BRAF V600E mutated allele was not preferentially associated with the development of metastases and the average mutated allele percentage decreased as the tumor progresses from the primary site to the lymph node metastatic sites. These observations support the need to reevaluate the role of the BRAF V600E mutation as a negative prognostic marker in PTCs.

SummaryObjective 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 (sPHPT) and 35 with familial PHPT (fPHPT) followed in eight Italian centres between October 2008 and March 2011. Measurements Albumin-adjusted serum calcium, PTH, 25OHD, 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 sPHPT and 2·75 ± 0·17 nmol/l in fPHPT patients (P = 0·007). The cinacalcet EMA labelling was met in 53% sPHPT and 26% fPHPT 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 sPHPT patients. Conversely, initial treatment (34%), persistent/relapsing PHPT after surgery (31%), and refusal of PTx (14%) were the indications in 79% fPHPT patients. Cinacalcet was started at 30 mg/daily in 64% of sPHPT and 91% of fPHPT 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 sPHPT and 80% of fPHPT) 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 fPHPT patients. Cinacalcet effectively reduces serum calcium in patients with either sPHPT or fPHPT.

Summary Papillary thyroid microcarcinoma generally carries an excellent prognosis, and fatal cases are becoming increasingly rare. Their pathologic and molecular features, however, remain largely unknown. We describe 3 cases of papillary thyroid microcarcinoma that, despite surgical and radioiodine treatment, recurred, metastasized, and eventually caused the death of the patients. In addition to morphology, immunohistochemical (cyclin D1 and p53) and molecular analyses ( BRAF [v-raf Murine sarcoma viral oncogene homolog B1], KRAS [V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog], HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homolog], NRAS [neuroblastoma RAS viral oncogene homolog], and PIK3CA [phosphoinositide-3-kinase, catalytic, alpha polypeptide]) were performed. Interestingly, all 3 cases presented with massive lymph node metastases that showed morphological evidence of "tumor progression" (tall cell features, poorly differentiated areas, and high-grade cytologic features). Cyclin D1 was consistently immunoreactive in both primary and metastatic site, whereas p53 was negative. BRAF V600E was absent in both sites, and KRAS , HRAS , NRAS , and PIK3CA were consistently wild type. These data suggest that, in cases of metastatic papillary thyroid microcarcinoma, an accurate morphologic analysis of the metastatic deposits could contribute to a more accurate prediction of tumor behavior.

Alcohol ablation, also known as percutaneous ethanol injection (PEI) and ethanol ablation (EA), has many applications for the treatment of endocrine neck diseases. Cell dehydration and protein denaturation, resulting in coagulative necrosis and fibrotic changes, are the immediate toxic effect induced by instillation of ethanol into the target tissue. EA is the first-line treatment for symptomatic cystic and predominantly cystic thyroid nodules. The efficacy of EA depends on a number of factors, e.g., the initial volume the lesion, the amount of ethanol instilled, the percentage of the solid component of the cyst. EA of thyroid cystic lesions is a safe procedure and no relevant side effects are usually recorded; nevertheless, being aware of the potential for recurrent laryngeal nerve (RLN) injury is required throughout the procedure. EA is not recommended for the treatment of either autonomously functioning thyroid nodules or solid cold thyroid nodules because of high recurrence rate, side effects, and the availability of other more effective ultrasound-guided interventional techniques. Regarding parathyroid (PT) lesions, EA can be used for treatment of large nonfunctional PT cysts and, in selected cases, for the treatment of hyperfunctioning PT glands in patients with chronic renal failure. Finally, EA can be used to treat metastatic lymph nodes from differentiated thyroid cancer in poor surgical candidates or patients seeking to avoid multiple reoperations.

The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFβ target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.

Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled.The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed.LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy.LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being.AACE = American Association of Clinical Endocrinologists FT3 = free triiodothyronine FT4 = free thyroxine LT3 = levotriiodothyronine LT4 = levothyroxine MeSH = medicine medical subject headings QoL = quality of life TSH = thyroid-stimulating hormone.

Idati epidemiologici indicano che l’ipoparatiroidismo post-chirurgico e la piu frequente tra le complicanze della chirurgia tiroidea. Si manifesta in percentuale variabile a seconda della casistiche, e puo essere transitorio o permanente. Il rischio di sviluppare ipocalcemia post-operatoria dipende principalmente dalla indicazione chirurgica (rischio superiore per malattia di Graves, inferiore in caso di carcinoma e di gozzo nodulare) e dalla estensione chirurgica (inferiore per tiroidectomia totale, superiore per svuotamento linfatico del compartimento centrale e del compartimento laterale). Non sono disponibili indicatori affidabili in grado di prevedere quali pazienti ipoparatiroidei lo rimarranno in modo stabile e quali invece recupereranno una normale funzione paratiroidea. Il trattamento si basa essenzialmente sulla somministrazione in dosi adeguate di calcitriolo e di calcio per via orale. La somministrazione endovenosa di calcio e riservata ai casi di ipocalcemia severa sintomatica. Normalmente si inizia il trattamento se la calcemia scende sotto i 7,8-8 mg/dl. I valori di calcemia vengono monitorati ogni 3–7 giorni, modificando la posologia dei farmaci in accordo con l’andamento della calcemia. Nella maggior parte dei casi l’ipoparatiroidismo e transitorio, ed e possibile ridurre progressivamente l’apporto esogeno di calcio e vitamina D fino a sospensione completa (strategia “reattiva”). Questo e l’atteggiamento piu diffuso, e comporta un certo numero di ipocalcemie sintomatiche. e stato riportato che un dosaggio di PTH eseguito 6 ore dopo la tiroidectomia e un indicatore affidabile dello sviluppo di successiva ipocalcemia. Qualora l’organizzazione locale consenta di disporre di questo dato, pertanto, e possibile iniziare trattamento precoce con calcitriolo/calcio in caso di riduzione del PTH di piu del 90% rispetto al valore basale (strategia “predittiva”). In alcuni Centri si procede a iniziare la somministrazione di calcitriolo/calcio a tutti i pazienti operati, a prescindere dai valori e dall’andamento della calcemia (strategia “preventiva”), evitando cosi l’insorgenza di ipocalcemia ma trattando anche pazienti che non ne avrebbero avuto necessita. Una scelta operativa pratica puo essere di adottare la strategia reattiva, riservando la strategia preventiva ai casi ad alto rischio di sviluppo di successiva ipocalcemia.

S. Piana, A. Frasoldati, M. Ferrari, R. Valcavi, E. Froio, V. Barbieri, C. Pedroni and G. Gardini Is a five-category reporting scheme for thyroid fine needle aspiration cytology accurate? Experience of over 18 000 FNAs reported at the same institution during 1998–2007 Objective: Fine needle aspiration (FNA) has long been recognized as an essential technique for the evaluation of thyroid nodules. Although specific cytological patterns have been recognized, a wide variety of reporting schemes for thyroid FNA results have been adopted. This study reports our experience with a five-category reporting scheme developed in-house based on a numeric score and applied to a large series of consecutive thyroid FNAs. It focuses mainly on the accuracy of thyroid FNA as a preoperative test in a large subset of histologically distinct thyroid lesions. Methods: During the 1998–2007 period, 18 359 thyroid ultrasound-guided FNAs were performed on 15 269 patients; FNA reports were classified according to a C1–C5 reporting scheme: non-diagnostic (C1), benign (C2), indeterminate (C3), suspicious (C4), and malignant (C5). Results: Non-diagnostic (C1) and indeterminate (C3) FNA results totalled 2 230 (12.1%) and 1 461 (7.9%), respectively, while suspicious (C4) and malignant (C5) results totalled 238 (1.3%) and 531 (2.9%), respectively. Histological results were available in 2 047 patients, with thyroid malignancy detected in 840. Positive predictive value of FNA was 98.1% with a 49.0 likelihood ratio (LR) of malignancy in patients with a C4/C5 FNA report. Conclusions: This five-category scheme for thyroid FNA is accurate in discriminating between the virtual certainty of malignancy associated with C5, a high rate (92%) of malignancy associated with C4, and a 98% probability of a histological benign diagnosis associated with C2. Further sub-classifications of C3 may improve the accuracy of the diagnostic scheme and may help in recognizing patients eligible for a ‘wait and see’ management.

A cohort of 1039 consecutive cases of thyroid carcinoma treated at a single institution and followed for an average of 11.9 years or until death included 102 encapsulated well-differentiated follicular-patterned tumors that had been diagnosed as carcinoma because of complete capsular invasion and/or papillary carcinoma-type nuclei. None of these cases were among the 67 patients from the cohort who died as a result of their thyroid carcinoma. The results of this study and a critical review of the pertinent literature indicate that tumors with these features are associated with an extremely favorable outcome and that they do not play a significant role in the fatality rate of thyroid carcinoma.

The last 20 years have observed the proposal of several minimally invasive techniques for non-surgical treatment of thyroid nodules. This chapter describes, on the basis of our experience and of a brief literature review, the efficacy, safety, cost-effectiveness and current clinical indications of the first of these procedures: percutaneous ethanol injection (PEIT).

To provide an overview of ultrasound (US)-guided percutaneous ethanol injection (PEI) therapy for thyroid cystic nodules and discuss the practical and technical details.We present preliminary data of a controlled randomized study involving 281 patients (221 women and 60 men; 18 to 85 years old) with benign thyroid cystic nodules. Study inclusion criteria were local discomfort or cosmetic damage, cystic volume more than 2 mL, 50% or more fluid component, benignity as confirmed by cytologic specimen obtained by US-guided fine-needle aspiration biopsy (FNAB), and euthyroidism. Exclusion criteria were inadequate, suspicious, or positive FNAB cytology, high serum calcitonin, and contralateral laryngeal cord palsy. By random assignment, 138 patients underwent simple cyst evacuation, and 143 underwent cyst evacuation plus PEI by a skilled operator using a US-guided technique. The amount of ethanol injected was 50 to 70% of the cystic fluid extracted.Before treatment, the mean (+/-SD) nodule volume was 19.0 +/- 19.0 mL versus 20.0 +/- 13.4 mL in the PEI versus the simple evacuation group (no significant difference). After 1 year, volumes were 5.5 +/- 11.7 mL versus 16.4 +/- 13.7 mL (P0.001), with a median 85.6% versus 7.3% reduction, respectively (P0.001), of the initial volume. The median nodule volume reduction after PEI was 88.8% and 65.8% in empty body and mixed thyroid cysts, respectively. Compressive and cosmetic symptoms disappeared in 74.8% and 80.0% of patients treated with PEI versus 24.4% and 37.4% of patients treated with simple evacuation, respectively (P0.001). Side effects were minor.These data provide definitive evidence that PEI is a safe and effective treatment for thyroid cystic nodules. Unicameral thyroid cysts are the most suitable candidate nodules for PEI.

L’iperparatiroidismo primitivo consiste in un’alterazione del metabolismo fosfo-calcico caratterizzata da una relativa e parzialmente incontrollata secrezione di paratormone (PTH) da parte di una o piu paratiroidi iperfunzionanti. La malattia si presenta in forma asintomatica in oltre l’ 80% dei casi; nefrolitiasi (15–20%) e osteopenia (20–25%) sono le manifestazioni cliniche piu frequenti. La storia naturale dell’iperparatiroidismo, in particolare nel paziente asintomatico, non e a tutt’oggi completamente delineata. Nel caso vi sia un’indicazione all’intervento chirurgico, la diagnosi biochimica di iperparatiroidismo viene seguita da indagini volte a localizzare la lesione responsabile. L’ecografia cervicale e in grado di identificare la patologia paratiroidea nel 70–85% dei casi. La scintigrafia mostra analoga sensibilita ed e particolarmente utile nell’identificare le lesioni paratiroidee a sede ectopica. L’agoaspirato paratiroideo, completato dal dosaggio di PTH sul liquido di lavaggio, permette di confermare l’origine paratiroidea di una lesione dimostrata in ecografia. Tutti i pazienti con iperparatiroidismo primitivo sintomatico sono candidati alla paratiroidectomia. Le indicazioni chirurgiche individuate dalla NIH Consensus Conference del 1990 sono state recentemente modificate in un workshop organizzato sulla gestione dell’iperparatiroidismo primitivo asintomatico, per quanto riguarda i valori soglia di incremento della calcemia e gli indici di riferimento nella valutazione della densita minerale ossea. Nei pazienti non sottoposti a intervento chirurgico, e necessario controllare, con la terapia medica, gli effetti sistemici della malattia, quali l’ipercalcemia e l’osteopenia.

ObjectiveTranscriptional 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 ofTERTpromoter 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.DesignWe analyzed the frequency ofTERTpromoter 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 betweenTERTpromoter mutations and BRAF V600E mutation was also investigated.MethodsTERTpromoter mutational status was evaluated by direct sequencing of the hotspot harboring the C228T and the C250T mutations.ResultsIn the overall cohort of 121 PTCs analyzed, 17% of cases (21/121) carried a mutation in theTERTpromoter. Noticeably, 33% of DM-PTCs were mutated in theTERTpromoter while only 9% of the control-PTCs showed a mutation in this locus. We also observed a positive association between BRAF V600E andTERTC228T mutations in the cohort of DM-PTCs.ConclusionsThese results indicate thatTERTpromoter mutations are associated with the development of distant metastases in PTCs and may help in predicting aggressive behavior in this type of tumor.

The aim of this study was to identify any possible predictive factors of lateral neck recurrence in patients with papillary thyroid carcinoma with no ultrasonographic and/or cytological evidence of lymph node metastasis at time of diagnosis. The influence of lateral neck recurrence on survival was also investigated.Observational retrospective study.Retrospective review of clinical records of 610 patients surgically treated for papillary thyroid carcinoma with clinically negative lymph nodes at the Otolaryngology Unit of the Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy, from January 1984 to December 2008.Lateral neck recurrences were ipsilateral to the primary tumor in all cases and were associated with the occurrence of more aggressive histological variants and central neck metastasis. Lateral neck recurrences were more frequently observed in patients with distant metastases and were associated with a reduced disease-specific survival.Lateral neck compartment ipsilateral to the tumor was the most common site of recurrence, with about half of cases appearing in the first 28 months of follow-up. In patients with papillary thyroid carcinoma, detection of lateral neck metastases prior to first surgery is crucial to surgical planning. Aggressive histological variants and postsurgical evidence of lymph node metastasis from papillary thyroid carcinoma in central neck compartment are associated with a higher risk of lateral neck recurrence. In these patients, a closer postsurgical ultrasound surveillance of the lateral neck compartments seems worthwhile.4.

We report two patients with incidentally discovered enlarged parathyroid glands while performing neck ultrasonography (US) for thyroid nodules. The parathyroid masses were seen as hypoechoic, homogeneous, oval nodules, separated from the thyroid gland. Both patients were completely asymptomatic, although subclinical evidence of hyperparathyroidism (serum PTH and calcium levels in the upper limit of the normal range, increased ionized serum calcium, osteocalcin, urinary calcium and hydroxyproline) was subsequently found in one patient. An enhanced uptake on sesta-MIBI scinti scan was concordant with the US finding in the two cases. PTH levels in the wash-out from the US-guided fine needle aspiration biopsy, confirmed the parathyroid origin of the lesions. Cytology and immunocytochemistry were, in our cases, unreliable diagnostic procedures. The extensive use of US imaging in thyroid pathology may increase the finding of US incidentally discovered parathyroid adenomas. The early detection of silent parathyroid pathologic findings may extend the natural history of these masses to a preclinical stage. Further investigations are necessary to evaluate the evolution of parathyroid incidentalomas and therefore their clinical significance.

The identification of metastatic neck lymph nodes in patients awaiting surgery for differentiated thyroid tumor permits their excision during thyroidectomy. In order to detect thyroid cancer lymphatic metastasis before surgery, we measured thyroglobulin (Tg) in the needle wash-out of fine-needle aspiration biopsy (FNAB). Ultrasound-guided FNAB on enlarged neck nodes was performed in 23 patients awaiting surgery for differentiated thyroid tumor (n = 33 lymph nodes), 47 patients previously thyroidectomized for thyroid tumor (n = 89 lymph nodes), and 60 patients without thyroid disease (n = 94 lymph nodes). Immediately after aspiration biopsy, the needle was rinsed with 1 mL of normal saline solution and Tg levels were measured on the needle wash-out (FNAB-Tg). FNAB-Tg levels were markedly elevated in metastatic lymph nodes both in patients awaiting thyroidectomy (metastatic vs. negative lymph nodes, mean +/- SEM, 16,593 +/- 7,050 ng/mL vs. 4.91 +/- 1.61 ng/mL; p0.001) and in thyroidectomized patients (11,541 +/- 7,283 ng/mL vs. 0.45 +/- 0.07 ng/mL; p0.001). FNAB-Tg sensitivity, evaluated through histological examination in 69 lymph nodes, was 84.0%. The combination of cytology plus FNAB-Tg increased FNAB sensitivity from 76% to 92.0%. In conclusion, FNAB-Tg measurement is a useful technique for early diagnosis of lymph node metastasis originating from differentiated thyroid cancer.

By means of semiquantitative immunocytochemistry, possible age-related changes in dopamine and cyclic AMP-regulated phosphoprotein mr 32 (DARPP-32) and glial fibrillary acidic protein (GFAP) immunoreactivities (IR) were investigated in tanycytes of the arcuate nucleus. These two markers showed opposite changes during aging. DARPP-32 IR decreased by around 70%, whereas GFAP IR increased by around 300% in 24-month-old vs. 3-month-old rats. These changes were accompanied by a progressive loss in the number of tanycytes, measured by counting of their long processes in the arcuate nucleus. No significant age-related change was observed either in GFAP IR in astrocytic populations of the mediobasal hypothalamus or in tyrosine hydroxylase IR in dopaminergic neurons of the dorsal arcuate nucleus. These observations indicate that the tanycytic population of the arcuate nucleus undergoes important modifications during aging, which include cell loss, impairment in the intracellular signalling cascade linked to DARPP-32, and hypertrophy. These changes may be related to the alterations in the neuroendocrine systems known to occur during aging.

Percutaneous ethanol injection (PEI) was first proposed about 30 years ago for sclerotherapy of different kind of lesions, such as hepatocellular carcinoma, hepatic and renal cysts, adrenal adenoma, and parathyroid hyperplasia. Ethanol exerts its sclerosing properties through cellular dehydration and protein denaturation, which lead to coagulative necrosis and small vessel thrombosis. As a consequence, hemorrhagic infarcts and reactive fibrosis are the prevailing histological changes described in tissues exposed to ethanol. In the thyroid gland, the first documented use of PEI for treating thyroid cysts dates to 1989 (Period Biol 91:1116–1118, 1989); shortly after, this technique was also suggested as an alternative therapeutic option to surgery and radioiodine for the treatment of autonomous functioning nodules. Since then, PEI sclerotherapy of thyroid cysts has gained a world-wide diffusion, whereas the fortunes of PEI as a candidate first-line therapy for toxic and pre-toxic solid nodules have gradually faded. PEI treatment of thyroid cysts will therefore constitute the heart of the present chapter. PEI has also proved to be quite effective in treating other neck lesions, like thyroglossal duct cysts, enlarged parathyroid glands, and metastatic lymph nodes. These applications of PEI will also be briefly discussed.

In this report, we compared endoscopic ultrasonography (EUS), multidetector CT (MDCT), and Ga-68 DOTATOC PET/CT in patients with neuroendocrine tumors (NETs). We report our experience with use of these methods in patients suspected to have duodenopancreatic primitive NET.Nineteen consecutive patients (mean age, 56; 21-80), who underwent both Ga-68 DOTATOC PET/CT and EUS between March 2007 and November 2008 were retrospectively included in the study (16 underwent MDCT). Suspicion of NET was confirmed by EUS-FNA and/or surgery. Operative characteristics of PET, EUS, and MDCT were compared.Twenty-three neuroendocrine lesions were diagnosed in 13/19 patients. EUS, PET, and MDCT correctly identified as affected 13/13 (100%), 12/13 (92%), and 10/11 (91%) patients, respectively. On a lesion basis, EUS, PET, and MDCT identified correctly as NETs 22/23 (96%), 20/23 (87%), and 13/18 (72%) lesions (P = 0.08 EUS vs. CT). Both on a patient and on a lesion basis, specificity was 67%, 83%, and 80% for EUS, PET, and MDCT, respectively.EUS, Ga-68 DOTATOC PET, and MDCT seem to have comparable accuracy in diagnosis of duodenopancreatic NET and their combination may allow an optimal preoperative diagnosis.

The management of thyroid papillary microcarcinoma (PMC) is controversial. Total thyroidectomy, thyroid lobectomy/isthmectomy, and even no treatment have been proposed. We investigated the clinical course and prognostic factors for disease recurrence and distant metastasis in 445 patients with PMC.Data from 445 patients diagnosed with PMC in the period from 1978 to 2003 were reviewed and analyzed. Total thyroidectomy was performed in 404 patients and loboisthmusectomy in 41. Neck dissection took place in 226 patients (49.7%), with 166 of only the central compartment and 60 of both the central and lateral compartments. Radioiodine ((131)I) ablation treatment was given to 389 patients.Median tumor size was 7 mm (range 1-10 mm). PMC was multifocal in 156 cases (35%) and bilateral in 60 cases (13.5%). Extrathyroidal tumor extension (pT3) and neck lymph node metastasis (pN1) were present in 133 (30%) and 182 (40.9%) patients, respectively. Capsular invasion without extrathyroidal tumor extension was observed in 39 (8.7%) patients. Mean follow-up was 5.3 (range 1-26) years. Seventeen (3.8%) patients had recurrence or persistence of disease: neck recurrence (NR) in 12 (2.7%), distant metastasis (DM) in four (0.9%), NR + DM in one (0.2%). One patient (0.2%) died of the disease. Capsular invasion, extrathyroidal tumor extension (pT3), and neck lymph node metastasis at presentation (pN1) were the only independent risk factors for NR and/or DM occurrence (p0.05). Patients not showing these features, who were treated with loboisthmusectomy only, never experienced disease recurrence.Total thyroidectomy seems advisable in PMC with extrathyroidal extension and neck lymph node metastasis at presentation. Capsular invasion without extrathyroidal extension may suggest aggressive tumor behavior and require radical treatment.

The term interventional thyroidology refers to minimally invasive ultrasound-guided techniques to treat diseases of the endocrine neck, i.e., diseases of thyroid and parathyroid glands. Laser ablation (LA) and radiofrequency ablation (RFA) are two of these procedures used to destroy thyroid nodules and tumors using hyperthermia without surgical removal. Indications of LA and RFA technique for the treatment of endocrine neck diseases include symptomatic benign cold thyroid nodules, symptomatic thyroid cysts, autonomously functioning thyroid nodules, and recurrent thyroid cancer. Both thermal techniques have also been used for the treatment of parathyroid adenomas, but with several drawbacks and are no longer recommended. The advantages of in situ tumor ablation are reduced costs, the possibility of performing procedures on outpatients, the possibility of treating patients who are poor candidates for surgery due to age or comorbidity, and the possibility of treating patients who refuse surgery. LA and RFA are performed by endocrinologists, interventional radiologists, and surgeons.

Percutaneous ethanol injection (PEI), also known as ethanol, or alcohol, ablation, is the first-line treatment for thyroid cystic nodules. Immediately after its instillation into the thyroid tissue, ethanol causes coagulative necrosis and fibrotic changes resulting in a stable and durable regression of the treated cystic lesion. Long-term effectiveness of PEI, along with its substantial safety, has been consistently documented by many studies published in the last decades: therefore this procedure has gained a worldwide diffusion. In parallel with the successful utilization of the sclerosing properties of ethanol in thyroid cystic nodules, PEI application for treatment of autonomously functioning thyroid nodules (AFTNs) or solid cold thyroid nodules has been progressively abandoned due to its poor efficacy, the not negligible risk of side effects, and the expanding use of other ultrasound-guided interventional techniques, namely, laser thermal ablation (LTA) and radio-frequency ablation (RFA). Ethanol ablation has also been used with good results for treating hyperplastic parathyroid (PT) glands in patients with chronic renal failure as well as large nonfunctioning PT cysts. In addition, in selected patients, metastatic lymph nodes from differentiated thyroid cancer can be treated with PEI as an alternative option to surgery.

Objective To assess the performance of neck ultrasonography (US) in the detection of lymph node lesions metastatic from differentiated thyroid carcinoma (DTC) and the detection of parathyroid adenomas. Methods Neck US was performed in 667 patients with DTC (173 men and 494 women; mean age, 47.7 years). In cases of suspicious neck nodes, US-guided fineneedle aspiration biopsy (US-FNAB) plus measurement of thyroglobulin in the needle washouts (FNAB-Tg) was done. In addition, 75 patients with primary hyperparathyroidism (pHPT) (15 men and 60 women; mean age, 56 years) underwent neck US and sestamibi scintiscanning for localization of parathyroid adenoma. For confirmation of US findings, US-FNAB plus measurement of parathyroid hormone in the needle washouts (FNAB-PTH) was performed. FNAB-PTH was also measured in 129 suspected parathyroid adenomas incidentally detected in a series of 4,129 patients undergoing neck US examination for thyroid disease. Results The presence of DTC metastatic lesions was confirmed in 46 of 95 patients with suspicious neck nodes. US sensitivity and specificity were 82.1% and 91.2%, respectively. The positive predictive value (PPV) of USFNAB + FNAB-Tg was 94.7%. In the 75 patients with pHPT, US followed by US-FNAB + FNAB-PTH showed a higher PPV (97.5%) in comparison with sestamibi scintiscanning (83.7%) in the detection of parathyroid adenoma. A parathyroid adenoma was also incidentally detected in 0.62% of the 4,129 patients undergoing neck US for thyroid disease. Conclusion US accurately detects DTC neck metastatic lesions and localizes parathyroid adenomas. Moreover, neck US may lead to discovery of parathyroid incidentalomas. (Endocr Pract. 2004;10:261-268)