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The term "nodular goiter" has long been used to refer to a nodular thyroid gland, based on the assumption that nodule growth may be associated with hyperplasia of the surrounding non-nodular tissue. The aim of this prospective, multicenter, observational study was to determine whether nodule growth is accompanied by growth in the non-nodular tissue.Eight Italian thyroid-disease referral centers enrolled 992 consecutive patients with one to four benign nodules. Nodular and non-nodular thyroid tissue volumes were assessed for five years with annual ultrasound examinations.In participants whose nodules remained stable (n = 839), thyroid volumes did not change (baseline 15.0 mL [confidence interval (CI) 14.5-15.6]; five-year evaluation 15.1 mL [CI 14.5-15.7]). In participants with significant growth of one or more nodule (n = 153), thyroid volumes increased and by year 5 were significantly greater than those of the former group (17.4 mL [CI 16-18.7]). In 76 individuals with unilateral nodules that grew, the mean nodular lobe volume significantly exceeded that of the contralateral lobe (8.6 mL [CI 7.4-9.8] vs. 6.7 mL [CI 6-7.4]). The unaffected lobe volumes remained stable over time, while nodular lobes grew steadily and were significantly greater at the end of follow-up (10.1 mL [CI 8.9-11.3]). Excluding the volume of the largest growing nodule in these cases, the remaining volume of the affected lobe remained virtually unchanged with respect to its baseline value. Furthermore, there was no significant difference in the non-nodular tissue volume between the unaffected lobe and the affected lobe (with the largest growing nodule volume subtracted), both at baseline and at the end of follow-up.The growth of thyroid nodules is a local process, not associated with growth of the surrounding non-nodular tissue. Therefore, a normal-sized thyroid containing nodules should be referred to as a "uni- or multinodular thyroid gland" and considered a distinct entity from "uni- or multinodular goiter."

Objective: The aim of this review was to analyze the existing literature concerning the relationship between Hashimoto thyroiditis (HT) and vestibular dysfunction. Methods: We used electronic databases (PubMed, EMBASE, Cochrane Library) to search and collect all published articles about the association between HT and vestibular disorders. Results: Several observational and retrospective studies have postulated a relationship between thyroid autoimmunity and vestibular disorders. In most cases, an appropriate control group was lacking, and the impact of thyroid functional status could not precisely be established. In recent years, two well-designed prospective studies have provided convincing evidence that the association is not random. One article reported that patients with Meniere disease (MD) had a significantly higher prevalence of positive anti-thyroid autoantibody as compared to healthy controls. Moreover, more than half of MD patients had either positive anti-thyroid or non–organ-specific autoantibody titers, compared to less than 30% of both patients with unilateral vestibular paresis without cochlear involvement and healthy controls. Another study found that patients with benign paroxysmal positional vertigo (BPPV) had significantly higher serum thyroid-stimulating hormone and antithyroid autoantibody levels than healthy controls. Additionally, almost one-fifth of euthyroid patients with HT had signs of BPPV. Conclusion: The published results indicate that patients with MD or BPPV are potential candidates to also develop HT. Thus, in HT patients, the presence of even slight symptoms or signs potentially related to vestibular lesions should be carefully investigated. Abbreviations: AITD = autoimmune thyroid disease; BPPV = benign paroxysmal positional vertigo; EH = endolymphatic hydrops; HT = Hashimoto thyroiditis; L-T4 = L-thyroxine; MD = Meniere disease; PS = Pendred syndrome; Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone

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

Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed.To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size.Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up.Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes0.2 to1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes ≥1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer.Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules.

Objective: The association between papillary thyroid cancer (PTC) and Hashimoto's thyroiditis is widely recognized, but less is known about the possible link between circulating anti-thyroglobulin antibody (TgAb) titers and PTC aggressiveness. To shed light on this issue, we retrospectively examined a large series of PTC patients with and without positive TgAb. Methods: Data on 220 TgAb-positive PTC patients (study cohort) were retrospectively collected in 10 hospital-based referral centers. All the patients had undergone near-total thyroidectomy with or without radioiodine remnant ablation. Tumor characteristics and long-term outcomes (follow-up range: 2.5–24.8 years) were compared with those recently reported in 1020 TgAb-negative PTC patients with similar demographic characteristics. We also assessed the impact on clinical outcome of early titer disappearance in the TgAb-positive group. Results: At baseline, the study cohort (mean age 45.9 years, range 12.5–84.1 years; 85% female) had a significantly higher prevalence of high-risk patients (6.9% vs. 3.2%, p

The current use of life-long follow-up in patients with papillary thyroid cancer (PTC) is based largely on the study of individuals diagnosed and treated in the latter half of the 20th century when recurrence rates were approximately 20% and relapses detected up to 20-30 years after surgery. Since then, however, diagnosis, treatment, and postoperative monitoring of PTC patients have evolved significantly.The objective of the study was to identify times to PTC recurrence and rates by which these relapses occurred in a more recent patient cohort.We retrospectively analyzed follow-up data for 1020 PTC patients consecutively diagnosed in 1990-2008 in 8 Italian hospital centers for thyroid disease. Patients underwent thyroidectomy, with or without radioiodine ablation of residual thyroid tissue and were followed up with periodic serum thyroglobulin assays and neck sonography.At the initial posttreatment (≤ 12 months) examination, 948 patients had no structural/functional evidence of disease. During follow-up (5.1-20.4 years; median 10.4 years), recurrence (cervical lymph nodes, thyroid bed) was diagnosed in 13 (1.4%) of these patients. All relapses occurred 8 or fewer years after treatment (10 within the first 5 years, 6 within the first 3 years). Recurrence was unrelated to the use/omission of postoperative radioiodine ablation.In PTC patients whose initial treatment produces disease remission (no structural evidence of disease), recurrent disease is rare, and it usually occurs during the early postoperative period. The picture of recurrence timing during the follow-up provides a foundation for the design of more cost-effective surveillance protocols for PTC patients.

Administration of radioiodine (I(131)) is currently exploited for both diagnostic and therapeutic treatment of thyroid cancer. Few data are available on the sodium/iodide symporter (NIS) expression in human testis, a particular important prerequisite to predict radioiodine accumulation in the gonads of males with thyroid cancer exposed to such a treatment. In this study, we analyzed the expression of NIS in mouse, rat and human normal testis in different stages of development. By using a quantitative RT-PCR, Western blot and immunohistochemical analysis, NIS mRNA and protein were measured in both fetal and adult testicular tissues. NIS transcript was detected in both fetal and adult testis, although its expression levels were approximately 10-fold less than in thyroid gland. Western blot analysis and immunohistochemistry showed the presence of NIS protein in germinal and Leydig cells, but not in Sertoli cells with prevalent expression in the cytosol compartment of the cells. Our study demonstrates that NIS transcript and protein are expressed in normal testis. Further studies will demonstrate whether it may act as the transporter of radioiodine in normal testis of male patients with thyroid cancer.

Context In multiple endocrine neoplasia (MEN), rearranged during transfection (RET), gene testing has been extensively exploited to characterize tumour aggressiveness and optimize the diagnostic and clinical management. Objective To report the underlying genetic alterations in an unusual case of MEN type 2 (MEN-2A). Design and patient Occult medullary thyroid carcinoma (MTC) was diagnosed in a 44-year-old man who had presented with unilateral phaeochromcytoma. DNA extracted from the blood and tumour tissues was analysed for mutations in RET. The transforming potential and mitogenic properties of the identified RET mutation were investigated. Results The patient carried a novel heterozygous germ-line RET mutation in exon 5 (Val292Met, GTG>ATG) (V292M/RET) with no evidence of additional somatic alterations. The mutation maps to the third cadherin-like domain of RET, which is usually not included in RET screening. Interestingly, MTC with concomitant phaeochromcytoma has never been associated with a RET mutation involving the extracellular cadherin-like domain. V292M/RET was absent in the only two relatives examined. In vitro assays indicate that the mutant has low-grade transforming potential. Conclusions Complete characterization and classification of all novel RET mutations are essential for extending genetic analysis in clinical practice. Our findings suggest that: (i) in all MEN-2 patients negative for RET hot-spot mutations, testing should be extended to all coding regions of the gene and (ii) the newly identified V292M/RET mutation is characterized by relatively weak in vitro transforming ability.

OBJECTIVE: Nonfunctioning thyroid nodules (NFTNs) display a diminished iodide-concentrating ability, owing to defective expression and cell membrane targeting of the sodium-iodide symporter (NIS). Since NIS expression is primarily modulated by thyroid iodine content in vitro and in animal models, we attempted to determine whether iodine supply influences the expression and localization of human NIS (hNIS) in NFTNs. DESIGN: Using immunohistochemistry, we analyzed cold hyperplastic nodules and nonnodular thyroid samples (controls) from patients living in iodine-sufficient (n = 19) or severely iodine-deficient (n = 15) areas. MAIN OUTCOME: Nodules from the iodine-sufficient area exhibited weak or absent hNIS immunostaining whereas almost all nodules from the iodine-deficient area were hNIS positive. Heterogeneous hNIS staining was common among the iodine-deficient samples (p = 0.028). hNIS was localized on membrane in all nodular samples from the iodine-deficient area and in less than 40% in the iodine-sufficient area. CONCLUSIONS: hNIS is adequately expressed and appropriately localized in NFTNs cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply.

Persistent or recurrent disease is rare in low risk patients with papillary thyroid cancer, and follow-up of these patients is a matter of debate. Neck ultrasonography (US), serum thyroglobulin (Tg), and whole body scan (WBS) after T(4) withdrawal were performed in 456 patients, followed up to 5 yr. At the end of the first year, 335 patients were Tg negative, and 121 were Tg positive; 65 of 96 patients with Tg levels between 1 and 10 ng/ml became spontaneously Tg negative after 2 yr. During follow-up, WBS discovered node metastases in 13 subjects, and US discovered node metastases in 38 subjects (31 Tg positive and 7 Tg negative). WBS did not add any information, because all WBS-positive patients were also US and Tg positive. Fifty percent of metastases were less than 1 cm and not palpable. Finally, the negative predictive value of both negative Tg and US at first follow-up was 98.8%. We suggest a first follow-up based upon US assessment and stimulated (after T(4) withdrawal or recombinant human TSH) serum Tg determination; subsequently, 1) US should not be mandatory at each examination in initially Tg- and US-negative subjects, but is strongly suggested in all other cases; 2) Tg determination should be repeated 1 yr later, after exogenous or endogenous TSH stimulation only in initially Tg-positive patients without any other evidence of residual disease; and 3) Tg measurement during therapy should be sufficient in all other cases.

The distribution of goiter prevalence in schoolchildren (no.=13,984, age 6-14 yr), the neonatal TSH results obtained from the congenital hypothyroidism screening program and the urinary iodine excretion values (no.=284) were employed for the assessment of iodine deficiency in Calabria, a Southern Italy region. Data were collected during the years 1990-1996. In the inland territory, goiter prevalence ranged from 19 to 64%. At sea level, there was a great variability of goiter prevalence, with values varying from 5.3 to 25.7%. The analysis of the neonatal hypothyroidism screening program data (no.=21,078) showed a 14.8% frequency of TSH levels5 microU/ml whole blood in newborns from the inland territory and a 14.1% frequency at sea level. Urinary iodine excretion resulted (mean+/-SD) 53.8+/-43.4 microg/l (range:20 to 189 microg/l) in the inland territory and 89.6+/-59.8 microg/l (range: 26 to 333 microg/l) at sea level. Median urinary iodine excretion values in 13 villages or small towns of the inland territory ranged from 31 to 57 microg/l. In 2 major towns located at sea level, the median iodine excretion values were 72 microg/l in Crotone main city and 94 microg/l in Reggio Calabria main city. The data indicated that moderate, with pockets of severe iodine deficiency is present in the inland region while iodine supply varies from sufficient to marginally low in the coastal areas. Mild iodine deficiency was found in a major town located at sea level.