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      Hyperfunctioning thyroid carcinoma: A systematic review

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          Abstract

          Hyperthyroidism may be caused by the development of primary or metastatic thyroid carcinoma. The aim of the present study was to collect recently reported cases of hyperfunctioning thyroid carcinoma in order to analyze its pathological characteristics, diagnostic procedures and treatment strategies. A PubMed ( https://www.ncbi.nlm.nih.gov/pubmed/) search was performed for studies published between January 1990 and July 2017. Full-text articles were identified using the terms, ‘hyperfunctioning thyroid carcinoma/cancer’, ‘malignant hot/toxic thyroid nodule’, or ‘hyperfunctioning papillary/follicular/Hürthle thyroid carcinoma’. Original research papers, case reports and review articles were included. Among all thyroid carcinoma cases included in the present study, the prevalence of follicular thyroid carcinoma (FTC) was ~10%; however, the prevalence of FTC among hyperfunctioning thyroid carcinomas was markedly higher (46.5% in primary and 71.4% in metastatic disease). The size of hyperfunctioning thyroid tumors was considerably larger compared with that of non-hyperfunctioning thyroid tumors, with a mean size of 4.25±2.12 cm in primary hyperfunctioning thyroid carcinomas. In addition, in cases of metastatic hyperfunctioning thyroid carcinoma, tumor metastases were widespread or large in size. The diagnosis of primary hyperfunctioning thyroid carcinoma is based on the following criteria: i) No improvement in thyrotoxicosis following radioactive iodine (RAI) treatment; ii) development of hypoechoic solid nodules with microcalcifications on ultrasound examination; iii) increase in tumor size over a short time period; iv) fixation of the tumor to adjacent structures; and v) signs/symptoms of tumor invasion. The diagnosis of metastatic hyperfunctioning thyroid carcinoma should be considered in patients suffering from thyrotoxicosis who present with a high number of metastatic lesions (as determined by whole-body scanning), or a history of total thyroidectomy. Surgery is the first-line treatment option for patients with primary hyperfunctioning thyroid carcinoma, as it does not only confirm the diagnosis following pathological examination, but also resolves thyrotoxicosis and is a curative cancer treatment. RAI is a suitable treatment option for patients with hyperfunctioning thyroid carcinoma who present with metastatic lesions.

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          Most cited references44

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          A solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma: review of the literature

          Hyperfunctioning nodules of the thyroid are thought to only rarely harbor thyroid cancer, and thus are infrequently biopsied. Here, we present the case of a patient with a hyperfunctioning thyroid nodule harboring thyroid carcinoma and, using MEDLINE literature searches, set out to determine the prevalence of and characteristics of malignant “hot” nodules as a group. Historical, biochemical and radiologic characteristics of the case subjects and their nodules were compared to those in cases of benign hyperfunctioning nodules. A literature review of surgical patients with solitary hyperfunctioning thyroid nodules managed by thyroid resection revealed an estimated 3.1% prevalence of malignancy. A separate literature search uncovered 76 cases of reported malignant hot thyroid nodules, besides the present case. Of these, 78% were female and mean age at time of diagnosis was 47 years. Mean nodule size was 4.13 ± 1.68 cm. Laboratory assessment revealed T3 elevation in 76.5%, T4 elevation in 51.9%, and subclinical hyperthyroidism in 13% of patients. Histological diagnosis was papillary thyroid carcinoma (PTC) in 57.1%, follicular thyroid carcinoma (FTC) in 36.4%, and Hurthle cell carcinoma in 7.8% of patients. Thus, hot thyroid nodules harbor a low but non-trivial rate of malignancy. Compared to individuals with benign hyperfunctioning thyroid nodules, those with malignant hyperfunctioning nodules are younger and more predominantly female. Also, FTC and Hurthle cell carcinoma are found more frequently in hot nodules than in general. We were unable to find any specific characteristics that could be used to distinguish between malignant and benign hot nodules.
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            Follicular carcinoma presenting as autonomous functioning thyroid nodule and containing an activating mutation of the TSH receptor (T620I) and a mutation of the Ki-RAS (G12C) genes.

            Most autonomous functioning thyroid nodules (AFTN) are benign thyroid follicular neoplasms. There are rare reports of malignant hot nodules, in which activating mutations of the TSH receptor (TSHR) were found. We report a case of follicular carcinoma presenting as an AFTN causing subclinical hyperthyroidism in a 64-year-old woman who had a 6-cm hot nodule in the left thyroid lobe. Genomic DNA was extracted from paraffin-embedded tissues from the tumor and extratumoral thyroid tissue. Sequence analyses revealed point mutations in two different genes: the normal ACC sequence at codon 620 of the TSHR gene was replaced by ATC, changing the threonine by isoleucine (T620I); and the wild-type GGT at codon 12 of Ki-RAS mutated to TGT, replacing glycine by cysteine (G12C). In transfection experiments the T620I mutant showed constitutive activity in terms of cyclic adenosine monophosphate (cAMP) production when permanently transfected in 3T3 cells. Here, we describe for the first time an activating mutation in 3codon 620 of the TSHR. In addition, the cancerous AFTN also contained a G12C Ki-RAS mutation. We hypothesize that the combination of these two mutations might have played an important role in both the hyperfunction of the tumor and the carcinogenetic process.
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              Papillary thyroid carcinoma in an autonomous hyperfunctioning thyroid nodule: case report and review of the literature.

              Whereas thyroid nodules are less common among children than among adults, the anxiety generated by the finding of a thyroid nodule is high because 20% of nodules found in children contain thyroid cancer. Discovery of a nodule in the context of hyperthyroidism is usually comforting due to the presumption that the nodule represents a benign toxic adenoma. An 11-year-old girl presented with heavy menses, fatigue, and a right thyroid mass. Laboratory evaluation revealed elevated triiodothyronine and undetectable thyroid-stimulating hormone. Thyroid ultrasonography revealed a 3.5 cm nonhomogenous nodule, and scintigraphy was consistent with an autonomous hyper-functioning nodule. Fine-needle aspiration biopsy could not rule out malignancy, and patient underwent right hemithyroidectomy and isthmusectomy. Pathology was consistent with papillary thyroid carcinoma. We report the discovery of papillary thyroid carcinoma in an autonomously hyperfunctioning nodule in an 11-year-old girl. Detection of an autonomously functioning thyroid nodule in children and adolescents does not exclude the possibility of thyroid carcinoma and warrants careful evaluation and appropriate therapy.
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                Author and article information

                Journal
                Mol Clin Oncol
                Mol Clin Oncol
                MCO
                Molecular and Clinical Oncology
                D.A. Spandidos
                2049-9450
                2049-9469
                December 2019
                01 October 2019
                01 October 2019
                : 11
                : 6
                : 535-550
                Affiliations
                [1 ]Department of Breast-Thyroid Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 201620, P.R. China
                [2 ]Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX 77030, USA
                Author notes
                Correspondence to: Dr Jun Liu, Department of Breast-Thyroid Surgery, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Songjiang, Shanghai 201620, P.R. China, E-mail: liujun95039@ 123456163.com
                Article
                MCO-0-0-1927
                10.3892/mco.2019.1927
                6870051
                c132e4b9-b5e3-4c0e-ae4a-1d5f27d2d6c5
                Copyright: © Liu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 31 January 2019
                : 06 August 2019
                Categories
                Articles

                thyroid carcinoma,hyperfunctioning thyroid carcinoma,malignant hot thyroid nodule,hyperthyroidism,metastasis

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