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Journal: Thyroid : official journal of the American Thyroid Association

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The increase in risk for late-onset thyroid cancer due to radiation exposure is a potential health effect after a nuclear power plant accident mainly due to the release of radioiodine in fallout. The risk is particularly elevated in those exposed during infancy and adolescence. To estimate the possibility and extent of thyroid cancer occurrence after exposure, it is of utmost importance to collect and analyze epidemiological information providing the basis for evaluation of radiation risk, and to consider radiobiology and molecular genetics. In this regard, the dose-response of cancer risk, temporal changes in the rates of thyroid cancer, its histopathological types and subtypes, and frequency of underlying genetic abnormalities are important. At present, however, it is difficult or impossible to distinguish radiation-induced thyroid cancer from spontaneous/sporadic thyroid cancer because molecular radiation signatures, biomarkers of radiation exposure or genetic factors specific to radiation-induced cancer are not identified yet. The large-scale ultrasound screening in Fukushima Prefecture of Japan demonstrated high detection rate of thyroid cancer in young individuals revealing 116 and 71 cases in the first and second rounds, respectively, among the same cohort of approximately 300,000 subjects. These findings raise concerns among residents and the public that it might be due to putative exposure to radiation from the accident at Fukushima Daiichi Nuclear Power Plant. Here we summarize evaluations by the international organizations and review scientific publications by the authors and others on childhood thyroid cancer, especially those relevant to radiation, including basic studies on molecular mechanisms of thyroid carcinogenesis. We also provide clinical details on surgical cases in Fukushima Prefecture and discuss the effect of thyroid ultrasound screening. Correct understanding of “radiation and the thyroid” issues are essential for interpretation of thyroid cancer in Fukushima.

Concepts: Genetics, Cancer, Chernobyl disaster, Coal, Prefectures of Japan, Fukushima Prefecture, Tōhoku region, Honshū

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Background: A systematic analysis of the clinical and pathologic patterns of childhood “sporadic” thyroid carcinoma in Belarus, in the absence of the “Chernobyl radioactive iodine factor,” has never been performed. The aim of this study was to establish the essential features of “sporadic” papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. Methods: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. Results: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). Conclusion: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

Concepts: Cancer, Oncology, Lymph node, Chernobyl disaster, Types of cancer, Tumor, Thyroid disease, Lymph

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Background: The most dreadful complication in thyroid surgery is bilateral recurrent laryngeal nerve paralysis, which can lead to transient or definitive tracheotomy. Methods: We implemented a strict standard operative procedure beginning January 2010 and modified our operative procedure: in all patients undergoing bilateral operation, we begin with the biggest side or with the cancerous/suspicious side without dissecting at all the contralateral side. In case of loss of intraoperative neuromonitoring (IONM) signal at the end of the first side after stimulation of the vagus nerve, we stop the procedure after the unilateral lobectomy, even when the recurrent nerve is anatomically intact and even in case of malignancy. In case of loss of the IONM signal, serial laryngoscopies are performed until recovery or definitive recurrent laryngeal nerve palsy is demonstrated. We report here our results in patients with loss of the IONM signal after lobectomy and discuss the medical implications in case of benign and malignant thyroid conditions. Results: Since January 2010, the operation was stopped at the first side in 9 out of 220 planned bilateral thyroidectomies. There were 5 benign thyroid conditions and 4 thyroid cancers, including 3 papillary thyroid cancers and 1 bilateral medullary thyroid cancer in a MEN2a patient. In 2 patients, it was a false positive IONM loss. One of these 2 patients had the other lobe removed at day 3. In 7 patients the laryngoscopy demonstrated total or partial laryngeal nerve palsy at day 1, but the recurrent nerve function recovered fully in all patients between 1 - 4 months post-operatively. All cancer patients were operated on the other side within 3 days to 3 months; 1 patient with a benign condition is followed conservatively. One of the 8 re-operated patients had transient recurrent nerve palsy post-operatively. Conclusion: In our opinion, the systematic use of IONM and the change in operative strategy will lead to an almost 0% rate of bilateral laryngeal nerve palsy at least in benign thyroid conditions. A loss of signal after the first side should lead to a stop of the procedure, also in cases of malignant conditions.

Concepts: Oncology, Recurrent laryngeal nerve

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Context: Graves' disease (GD) and Hashimoto´s thyroiditis (HT) are the most common autoimmune thyroid diseases (AITD). The exact etiology of the immune response to the thyroid is still unknown. MicroRNAs (miRNAs) critically control gene-expression. It has become evident that some miRNAs play an important role in regulating the immune response, as well as immune cell development. However, data on the role of miRNAs in autoimmune thyroid diseases are lacking. Objective: The aim of this study was to determine levels of key immunoregulatory miRNAs in thyroid glands of AITD patients and healthy controls Design: Several miRNAs were amplified by a semiquantitative TaqMan PCR from fine needle aspiration biopsies of thyroid tissue of 28 patients with GD, HT, and healthy controls. Results: miRNA 146a1 is significantly decreased in the thyroid tissue of GD (mean relative expression 5,17 in GD group vs. 8,37 in controls, p = 0.019) whereas miRNA 200a1 is significantly decreased (mean 8,30 in HT group vs. 11,20 in controls, p = 0.001) and miRNA 155 2 is significantly increased (mean 12,02 in HT group vs. 8,01 in controls, p = 0.016) in the thyroid tissue of HT compared to controls. Conclusion: Although limited by small sample size and some other limitations (e.g. missing matching for age and medication), our preliminary data open up a new field of research concerning miRNAs in thyroid diseases. Further studies in this interesting field are clearly warranted.

Concepts: Immune system, Medicine, Immunology, Thyroid disease, Hyperthyroidism, Thyroid, Graves' disease, Needle aspiration biopsy

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Background Chronic sialadenitis is one of the most frequent chronic complications after radioiodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGS) taken before and at 5 yrs after a RAI ablation. Methods SGS was performed just before RIA (pre-SGS) and approximately 5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (US) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in US and EF between the two SGS. Xerostomia were assessed and compared with the SGS findings. Results Worsening of the US was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients showed a worsening US for at least 1 of 4 salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least 1 of the 4 salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia were more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, P<0.05). The number of dysfunctional salivary glands was correlated with xerostomia (P<0.01). Conclusion About 20% of the salivary glands were dysfunctional on SGS at 5 years after a single RAI ablation, especially in patients who received higher doses of radioiodine. While parotid glands are more susceptible to I-131 related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.

Concepts: Sjögren's syndrome, Parotid gland, Salivary gland, Submandibular gland, Sublingual gland, Mumps, Serous fluid

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Background: Among euthyroid pregnant women in a large clinical trial, free thyroxine (FT4) measurements below the 2.5th centile were associated with a 17 lb higher weight (2.9 kg/m2) than in the overall study population. We explore this relationship further. Methods: Among 9351 women with second trimester thyrotropin (TSH) measurements between 1st and 98th centiles, we examine: 1) the weight/FT4 relationship; 2) percentages of women in three weight categories at each FT4 decile; 3) FT4 concentrations in three weight categories at each TSH decile; and 4) impact of adjusting FT4 for weight - in the reference group and in 190 subjects with elevated TSH measurements. Results: FT4 values decrease steadily as weight increases (p<0.0001 by ANOVA) among women in the reference group (TSH 0.05 - 3.8 IU/L). TSH follows no consistent pattern with weight. When stratified into weight tertiles, 48% of women at the lowest FT4 decile are heavy; the percentage decreases steadily to 22% at the highest FT4 decile. Median FT4 is lowest in heaviest women regardless of TSH level. In the reference group, weight adjustment reduces overall variance by 2.96%. Fewer FT4 measurements are at either extreme [below 5th FT4 centile - 4.8% before adjustment, 4.7% after adjustment; above 95th FT4 centile - 5.0% and 4.7%, respectively]. Adjustment places more light weight women and fewer heavy women below 5th FT4 centile; the converse above the 95th centile. Between TSH 3.8 and 5 IU/L, the FT4 percentage below 5th FT4 centile is not elevated (3.8% before adjustment, 3.1% after adjustment). Percentage of FT4 values above the 95th centile, however, is lower (1.5% before adjustment, 0.8% after adjustment). Above TSH 5 IU/L, 25% of women have FT4 values below the 5th FT4 centile; weight adjustment raises this to 30%; no FT4 values remain above the 95th FT4 centile. Conclusions: During early pregnancy, TSH values are not associated with weight, unlike non-pregnant adults. Lower average FT4 values among heavy women at all TSH deciles partially explain inter-individual differences in FT4 reference ranges. The continuous reciprocal relationship between weight and FT4 explains lower FT4 with higher weight. Weight adjustment refines FT4 interpretation.

Concepts: Pregnancy, Childbirth, Thyroid-stimulating hormone, Decile, Percentile, Median, Quantile, Concentration

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Background: There is a concern regarding the use of iodinated contrast agents (ICA) for chest and neck computed tomography (CT) to localize metastatases in patients with differentiated thyroid cancer (DTC). This is because the iodine in ICA can compete with (131)I and interfere with subsequent whole scans or radioactive iodine treatment. The required period for patients to eliminate the excess iodine is not clear. Therefore, knowing the period for iodine levels to return to baseline after the injection of ICA would permit a more reliable indication of CT for DTC patients. The most widely used marker to assess the plasmatic iodine pool is the urinary iodine (UI) concentration, which can be collected over a period of 24 hours (24U) or as a single-spot urinary sample (sU). As 24U collections are more difficult to perform, sU samples are preferable. It has not been established, however, if the measurement of iodine in sU is accurate for situations of excess iodine. Methods: We evaluated 25 patients with DTC who received ICA to perform chest or neck CT. They collected 24U and sU urinary samples before the CT scan and 1 week and 1, 2, and 3 months after the test. UI was quantified by a semiautomated colorimetric method. Results: Baseline median UI levels were 21.8 μg/dL for 24U and 26 μg/dL for sU. One week after ICA, UI median levels were very high for all patients, 800 μg/dL. One month after ICA, however, UI median levels returned to baseline in all patients, 19.0 μg/dL for 24U and 20 μg/dL for sU. Although the values of median UI obtained from sU and 24U samples were signicantly different, we observed a significant correlation between samples collected in 24U and sU in all evaluated periods. Conclusion: One month is required for UI to return to its baseline value after the use of ICA and for patients (after total thyroidectomy and radioiodine therapy) to eliminate the excess of iodine. In addition, sU samples, although not statistically similar to 24U values, can be used as a good marker to evaluate patients suspected of contamination with iodine.

Concepts: Chernobyl disaster, Nuclear medicine, Isotopes of iodine, Medical imaging, Radiography, Iodine, Iodine-131, Iodine-129

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Background: Medullary thyroid carcinoma (MTC) is characterized by the synthesis and secretion of calcitonin (Ct). MTC without Ct secretion has been reported on rare occasions. The aim of this study was to analyze the prevalence and clinical spectrum of nonsecretory MTC in two tertiary centers that cared for 839 patients with sporadic MTC. Methods: Clinical, biochemical, histological and immunohistological findings, and somatic RET mutations were analyzed, and long-term follow-up was documented. Results: Seven patients with nonsecretory MTC were identified among 839 patients with sporadic MTC; thus, the prevalence rate of of nonsecretory MTC was 0.83%. In these seven patients, Ct and carcinoembryonic antigen (CEA) levels were normal when the patients were initially diagnosed with MTC, despite advanced tumor stage. Ct and CEA levels remained undetectable in four patients, recurrence was indicated in one patient after 10 years of follow-up by routine anatomic imaging and increased CEA levels, and Ct levels became slightly elevated during follow-up, despite massive tumor load, in the remaining two patients. The diagnosis of MTC was confirmed by positive immunohistochemistry for Ct, CEA, and chromogranin A. A high Ki-67 proliferation index (three patients) and a high proportion of RET 918 mutated cells (four patients), as well as poorly differentiated histology, were associated with aggressive biological behavior of the MTC. The prognosis for nonsecretory MTC varied between long-term survival (12.5 years) and rapid progression leading to death within 1.75 years after diagnosis. Conclusions: The prevalence of nonsecretory MTC was low (0.83% of patients with MTC). Diagnosis was often made at a clinically advanced tumor stage. The histological and immunohistological characteristics and the clinical course and prognosis of nonsecretory MTC are markedly heterogeneous. A high Ki-67 proliferation index and a large proportion of cells with RET 918 mutations is associated with a poor prognosis.

Concepts: Cancer, Lung cancer, Medical terms, Anatomical pathology, Histology, Anatomy, Carcinoembryonic antigen, Medullary thyroid cancer

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Background: Several studies have evaluated the ability of ultrasound elastography (USE) to diagnose malignant nodules. However, these studies had important limiting factors, selection bias and small sample size. The aims of the present study were to prospectively assess, in a large group of patients, the diagnostic power of USE for detecting malignancy in thyroid nodules, and to compare this technique with B-mode grayscale ultrasonography (BUS) and power Doppler ultrasonography (PD). Method: There were 194 patients with 237 thyroid nodules who were examined using BUS, PD, and USE. USE scores were classified according to the elasticity: score 1 as high, score 2 as intermediate, and score 3 as low (i.e., a high degree of stiffness). Fine-needle aspiration cytology (FNAC) was performed in all nodules at least two different times. Nodules having two benign FNAC readings that did not change the diameter during a 6-month follow-up period were classified as benign. Patients having thyroid nodules with indeterminate, suspicious, or malignant cytology had total or hemithyroidectomy to remove the nodule and treat the malignancy. Results: Fifty eight (25%) nodules in 45 (23%) patients were found to be malignant. USE had a limited sensitivity and a positive predictive value in detecting malignant thyroid nodules and was not superior to BUS. USE had almost the same specificity and a negative predictive value as BUS. A power Doppler type-3 pattern was not of sufficient sensitivity to detect malignancies in thyroid nodules. Conclusions: In contrast to earlier reports, this current study noted a lower sensitivity and specificity of USE for the diagnosis of malignancy in thyroid nodules than previously reported.

Concepts: Positive predictive value, Negative predictive value, Medical imaging, Type I and type II errors, Sensitivity and specificity, Medical ultrasonography, Binary classification, Specificity

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Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself.

Concepts: Gene, Thyroid disease, Hyperthyroidism, Thyroid, Autoimmune disease, Graves' disease, Thyroidectomy, Graves' ophthalmopathy