scholarly journals Functioning and Nonfunctioning Thyroid Adenomas Involve Different Molecular Pathogenetic Mechanisms1

1999 ◽  
Vol 84 (11) ◽  
pp. 4155-4158
Author(s):  
Massimo Tonacchera ◽  
Paolo Vitti ◽  
Patrizia Agretti ◽  
Giovanni Ceccarini ◽  
Anna Perri ◽  
...  
Keyword(s):  
Thyroid Nodules ◽  
Direct Sequencing ◽  
Gross Anatomy ◽  
Follicular Carcinoma ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Cells ◽  
Activating Mutations ◽  
Gsα Gene ◽  
Thyroid Adenomas ◽  
Tshr Gene

The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gsα genes may confer TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and nonfunctioning follicular thyroid adenomas specifically selected for their homogeneous gross anatomy (single nodule in an otherwise normal thyroid gland). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codons 201 and 227 of the Gsα gene were also analyzed. At histology, all hyperfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed as follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features indicating malignant transformation (a minimally invasive follicular carcinoma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyperfunctioning follicular thyroid adenomas. In one hyperfunctioning adenoma, which was negative for TShR mutations, a mutation in codon 227 of the Gsα gene was identified. At variance with hyperfunctioning thyroid adenomas, no mutation of the TShR or Gsα genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings clearly define a different molecular pathogenetic mechanism in hyperfunctioning and nonfunctioning follicular thyroid adenomas. Activation of the cAMP cascade, which leads to proliferation but maintains differentiation of follicular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gsα genes are probably involved in nonfunctioning follicular adenomas.

scholarly journals A Rare Case of Heterozygous Gain of Function Thyrotropin Receptor Mutation Associated with Development of Thyroid Follicular Carcinoma

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
James Blackburn ◽  
Dinesh Giri ◽  
Barbara Ciolka ◽  
Nicole Gossan ◽  
Mohammad Didi ◽  
...  
Keyword(s):  
Thyroid Nodule ◽  
Clinical Presentation ◽  
Follicular Carcinoma ◽  
Thyroid Function Tests ◽  
Thyrotropin Receptor ◽  
Nuclear Pleomorphism ◽  
Activating Mutations ◽  
Thyroid Adenomas ◽  
Thyroid Follicular Carcinoma ◽  
First Time

Activating mutations in thyrotropin receptor (TSHR) have been previously described in the context of nonautoimmune hyperthyroidism and thyroid adenomas. We describe, for the first time, a mutation inTSHRcontributing to follicular thyroid carcinoma (FTC) in an adolescent. A 12-year-old girl presented with a right-sided neck swelling, increasing in size over the previous four weeks. Clinical examination revealed a firm, nontender thyroid nodule. Ultrasound scan of the thyroid showed a heterogeneous highly vascular mass. Thyroid function tests showed suppressed TSH [<0.03mU/L], normal FT4 [10.1pmol/L, 9-19], and raised FT3 [9.1pmol/L, 3.6-6.4]. Thyroid [TPO and TRAB] antibodies were negative. A right hemithyroidectomy was performed and the histology of the sample revealed follicular carcinoma with mild to moderate nuclear pleomorphism and evidence of capsular and vascular invasion (pT1b). Sanger sequencing of DNA extracted from the tumour tissue revealed a missense somatic mutation (c.1703T>C, p.Ile568Thr) inTSHR. Papillary thyroid carcinomas constitute the most common thyroid malignancy in childhood, while FTC is rare. FTC due toTSHRmutation suggests an underlying, yet to be explored, molecular pathway leading to the development of malignancy. The case is also unique in that the clinical presentation of FTC as a toxic thyroid nodule has not been previously reported in children.

scholarly journals Comparative study on association between serum TSH concentration and Thyroid cancer

2017 ◽  
Vol 4 (8) ◽  
pp. 2800
Author(s):  
Prasad C. ◽  
Supreet Kumar ◽  
Tej Tej Y.
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Tertiary Care ◽  
Follicular Carcinoma ◽  
Thyroid Stimulating Hormone ◽  
P Value ◽  
Thyroid Malignancy ◽  
Tertiary Care Centre ◽  
Serum Tsh ◽  
Tsh Levels

Background: In India, thyroid cancer accounts for less than 1% of all malignancies (2% of women and 0.5% of men). Thyroid cancer is responsible for 6 deaths per 1 million persons annually. Serum TSH is a well-established growth factor for thyroid nodules, however its role in thyroid malignancy is inconclusive hence this study was conducted with the objective to determine the association between serum Thyroid stimulating hormone (TSH) concentrations with thyroid carcinoma.Methods: Case control study was conducted in a tertiary care centre. 120 Benign and malignant thyroid subjects respectively were included in the study. Newly diagnosed and record based data collection was done. Measurements of serum TSH concentrations were performed by automated immune chemiluminescent assay. Data was analyzed using SPSS 22 version software, Chi-square test was used as test of significance for qualitative data, p value of <0.05 was considered as statistically significant.Results: Majority of them were females in the age group 26 to 40 years in both the groups and were diagnosed to have solitary thyroid nodule. In malignant thyroid nodules 51.7% were diagnosed to have follicular carcinoma, 46.7% had papillary carcinoma and 1.7% were diagnosed to have Hurthle cell carcinoma. Significant association was observed between TSH levels and diagnosis of thyroid lesions. TSH was raised (>4mIU/L) in 46.6% of malignant nodules and in 15% of benign nodules. Raised TSH had an odds ratio of 4.958 for Thyroid malignancy compared to benign nodulesConclusions: Higher TSH levels were associated with Thyroid malignancy and the risk of malignancy rises in parallel with serum TSH within normal range, and high levels of serum TSH concentrations was associated with advanced stage of thyroid cancer. 

scholarly journals WOMEN IN CANCER THEMATIC REVIEW: Thyroid-stimulating hormone in thyroid cancer: does it matter?

2016 ◽  
Vol 23 (11) ◽  
pp. T109-T121 ◽  
Author(s):  
Hannah Nieto ◽  
Kristien Boelaert
Keyword(s):  
Thyroid Cancer ◽  
High Risk ◽  
Thyroid Nodules ◽  
Cancer Recurrence ◽  
Needle Aspiration ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Cells ◽  
Invasive Approach ◽  
Serum Tsh ◽  
Stimulating Hormone

Differentiated thyroid cancer is the most common endocrine malignancy and the incidence is increasing rapidly worldwide. Appropriate diagnosis and post-treatment monitoring of patients with thyroid tumours are critical. Fine needle aspiration cytology remains the gold standard for diagnosing thyroid cancer, and although there have been significant refinements to this technique, diagnostic surgery is often required for patients suspected to have malignancy. Serum thyroid-stimulating hormone (TSH) is higher in patients with malignant thyroid nodules than in those with benign disease, and TSH is proportionally increased in more aggressive tumours. Importantly, we have shown that the pre-operative serum TSH concentration independently predicts the presence of malignancy in subjects presenting with thyroid nodules. Establishing the use of TSH measurements in algorithms identifying high-risk thyroid nodules in routine clinical practice represents an exciting, cost-efficient and non-invasive approach to optimise thyroid cancer diagnosis. Binding of TSH to receptors on thyrocytes stimulates a number of growth promoting pathways both in normal and malignant thyroid cells, and TSH suppression with high doses of levothyroxine is routinely used after thyroidectomy to prevent cancer recurrence, especially in high-risk tumours. This review examines the relationship between serum TSH and thyroid cancer and reflects on the clinical potential of TSH measurements in diagnosis and disease monitoring.

scholarly journals Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway

2003 ◽  
pp. 287-292 ◽  
Author(s):  
NA Georgopoulos ◽  
GP Sykiotis ◽  
A Sgourou ◽  
A Papachatzopoulou ◽  
KB Markou ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Direct Sequencing ◽  
Iodine Intake ◽  
Thyroid Stimulating Hormone ◽  
Gain Of Function ◽  
Autoimmune Thyroid ◽  
Activating Mutations ◽  
Clinical Presentations ◽  
Activating Mutation ◽  
Autonomously Functioning Thyroid Nodules

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.

scholarly journals Identification of Constitutively Activating Somatic Thyrotropin Receptor Mutations in a Subset of Toxic Multinodular Goiters1

1997 ◽  
Vol 82 (12) ◽  
pp. 4229-4233 ◽  
Author(s):  
Hans-Peter Holzapfel ◽  
Dagmar Führer ◽  
Peter Wonerow ◽  
Gerhard Weinland ◽  
Werner A. Scherbaum ◽  
...  
Keyword(s):  
Multinodular Goiter ◽  
The Other ◽  
Tsh Receptor ◽  
Surrounding Tissue ◽  
Additional Patient ◽  
Thyrotropin Receptor ◽  
Activating Mutations ◽  
Gsα Gene ◽  
Toxic Multinodular Goiter ◽  
Tshr Gene

Constitutively activating mutations in the TSH receptor (TSHR) gene and in the Gsα gene are frequent molecular causes for solitary toxic nodules of the thyroid. However, the etiology of toxic multinodular goiter is still largely unknown. Therefore, DNA from nodular and quiescent surrounding tissue of six patients with toxic multinodular goiters was screened for mutations in exons 9 and 10 of the TSHR gene and exons 7–10 of the Gsα gene by direct automated sequencing. In one patient, two different somatic TSHR mutations were identified in two different toxic nodules (L632I and F631L). In another patient, two different toxic nodules harbored the same TSHR mutation (I630L), whereas only one TSHR mutation (F631L) was identified in one of the two toxic nodules of an additional patient. In the other three patients, no mutations could be found in exons 9 and 10 of the TSHR gene or in exons 7–10 of the Gsα gene. Our results demonstrate that not only solitary toxic adenomas but also toxic multinodular goiters can be caused by constitutively activating mutations of the TSHR. In addition to mutations in the TSHR and possibly in Gsα, there are probably other still unknown mechanisms that cause hot nodules in toxic multinodular goiters.

scholarly journals Raman Spectroscopy Discloses Altered Molecular Profile in Thyroid Adenomas

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 43
Author(s):  
Armida Sodo ◽  
Martina Verri ◽  
Andrea Palermo ◽  
Anda Mihaela Naciu ◽  
Marialuisa Sponziello ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Thyroid Nodules ◽  
Thyroid Neoplasms ◽  
Molecular Profile ◽  
Molecular Fingerprint ◽  
Extensive Evaluation ◽  
Associated Proteins ◽  
Thyroid Adenomas ◽  
Malignant Lesions ◽  
Nuclear Features

Follicular patterned nodules are sometimes complex to be classified due to ambiguous nuclear features and/or questionable capsular or vascular invasion. In this setting, there is a poor inter-observer concordance even among expert pathologists. Raman spectroscopy was recently used to separate benign and malignant thyroid nodules based on their molecular fingerprint; anyway, some histologically proved follicular adenomas were clustered as having a characteristic profile of malignant lesions. In this study, we analyzed five follicular thyroid adenomas with a malignant spectroscopic profile compared to five follicular adenomas with a benign Raman spectrum in order to assess possible molecular differences between the two groups. Morphological, immunohistochemical, and molecular analyses evidenced expression of malignancy-associated proteins in four out of five malignant clustered adenomas. The remaining malignant clustered adenoma showed a TSHR mutation previously associated with autonomously functioning follicular carcinomas. In conclusion, thyroid follicular adenomas are a group of morphologically benign neoplasms that may have altered the mutational or expression profile; cases of adenomas with altered immunophenotype are recognized as showing a profile associated with malignancy by Raman spectroscopy. This correlation warrants a more extensive evaluation and suggests a potential predictive value of spectroscopic assessment in recognizing characteristics associated with tumor progression in follicular thyroid neoplasms.

scholarly journals TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population

2015 ◽  
Vol 22 (6) ◽  
pp. 901-908 ◽  
Author(s):  
Ebtesam Qasem ◽  
Avaniyapuram Kannan Murugan ◽  
Hindi Al-Hindi ◽  
Mingzhao Xing ◽  
Mai Almohanna ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Middle East ◽  
Direct Sequencing ◽  
Tumour Size ◽  
Middle Eastern ◽  
Middle Eastern Population ◽  
Thyroid Adenomas ◽  
Cell Variant ◽  
Hürthle Cell Thyroid Cancer ◽  
Promoter Mutations

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group. We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (≥45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAFV600E mutation and persistent/recurrent disease at 6–12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAFV600E mutation, and disease persistence/recurrence than the WT TERT.

The Preservation of Specialization by Dispersed Steer Thyroidal Cells in Long-Term Culture

1971 ◽  
Vol 9 (1) ◽  
pp. 49-69
Author(s):  
E. SIEGEL
Keyword(s):  
Standard Deviation ◽  
Trichloroacetic Acid ◽  
Doubling Time ◽  
Ultrastructural Level ◽  
Thyroid Stimulating Hormone ◽  
Linear Variation ◽  
Thyroid Cells ◽  
Long Acting ◽  
Number Of Cells

Serially propagated cells derived from the steer thyroid gland preserve several specialized characteristics, some demonstrable for as long as 8 months (over 15 passes). For about 5 passes (3 months), follicular-like arrays of cells develop. Thyroid-stimulating hormone (TSH) or thyrotropin (1 and 10 mu./ml) induces the formation of supernumerary nucleoli, and promotes at the ultrastructural level the prompt (within 10 min) appearance of microvilli, pseudopodia, and intracytoplasmic droplets. These cells have a mean plating efficiency (PE) of 16.5 ± 4.5% (standard deviation) and with 3x104 cells as the standard inoculum, a mean doubling time (Td) of 43.7 ± 1.2 h. The linear variation of Td with the number of cells seeded probably signifies strong cell-cell interactions. TSH (1-5o mu./ml) influences both PE and Td, with 1 mu./ml producing the maximum stimulation. TSH (0.001-100 mu./ml) also induces the discharge of incorporated radio-iodide from the cultured thyroid cells, achieving a peak by 2-4 h, titres of 0.1-1 mu./ml being most potent. Long-acting thyroid stimulator (LATS) (0.2 u./ml) likewise effects release of 131I into growth medium (1 experiment), but over a more protracted period. After labelling with [3H]leucine, radioautographs demonstrate that the synthesis of proteins is stimulated by exposure to TSH (1 mu./ml). Precipitation with trichloroacetic acid indicates that these cells persist in synthesizing 131I-tagged iodoproteins, an activity optimally stimulated by 1 mu./ml TSH and marked by 3 h. Hence, such thyroidal cell lines afford a useful model for studying differentiation and hormonal effects.

scholarly journals Is it possible to eliminate the number of inappropriate thyroid surgeries combining scintigraphy and cytology?

2021 ◽  
Vol 3 (5) ◽  
pp. 01-03
Author(s):  
Smaroula Divani
Keyword(s):  
Fine Needle Aspiration ◽  
Fine Needle Aspiration Cytology ◽  
Thyroid Nodules ◽  
Follicular Carcinoma ◽  
Accurate Method ◽  
Needle Aspiration ◽  
Aspiration Cytology ◽  
Fine Needle ◽  
Needle Aspiration Cytology ◽  
Indeterminate Cytology

Objective: Although fine needle aspiration cytology (FNAC) is the most reliable, safe and accurate method for the clinical management of abnormal thyroid nodules, 5%-15% of cases lead to indeterminate diagnoses and surgery is the recommended practice for them as they may be malignant. Nevertheless, the majority of cases with indeterminate cytology are benign, so the risk of unnecessary surgery is significant. In our study we combined FNAC and scintigraphy in order to reduce the number of inappropriate surgeries. Subjects and Methods: From 219 patients with thyroid fine needle aspiration cytology 33(9 males and 24 females) aged 18-73 years, had indeterminate FNAC diagnoses and were referred for scintigraphy. Surgery was performed in all cases. The results of FNAC, scintigraphy and histology were collected and compared. Results: From 33 cases with indeterminate cytology 32 had a benign histological diagnosis and only one was malignant (follicular Ca). That case had a positive scan. All cases with negative thyroid scans (29/33) were benign. False positive scans were 3, whereas one scan was true positive with final diagnosis follicular carcinoma. Conclusion: This study showed that combining the FNAC with the thyroid scintigraphy in cases of thyroid nodules with indeterminate cytology it is possible to reduce the number of inappropriate surgeries from 32 to 3.

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