ETJ differentiated thyroid cancer collection

 

Differentiated thyroid cancer is the commonest of endocrine tumours, and in recent years we have become increasingly aware of the potential for overtreatment. This topic collection brings together the most recent research advances in differentiated thyroid.

If you are interested in contributing an original research article to this collection, please submit your article proposal to etj@bioscientifica.com.

 

Explore all European Thyroid Journal Special Collections

 

Differentiated thyroid cancer

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Giulia Brigante Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria, Modena, Italy

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Clara Lazzaretti Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

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Elia Paradiso Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

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Federico Nuzzo Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

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Martina Sitti Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

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Frank Tüttelmann Institute of Reproductive Genetics, University of Münster, Münster, Germany

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Gabriele Moretti Department of Biology, University of Pisa, Pisa, Italy

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Roberto Silvestri Department of Biology, University of Pisa, Pisa, Italy

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Federica Gemignani Department of Biology, University of Pisa, Pisa, Italy

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Asta Försti Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany

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Kari Hemminki Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

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Rossella Elisei Department of Endocrinology, University Hospital, Pisa, Italy

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Cristina Romei Department of Endocrinology, University Hospital, Pisa, Italy

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Eric Adriano Zizzi PolitoBIO Med Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Italy

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Marco Agostino Deriu PolitoBIO Med Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Italy

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Manuela Simoni Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria, Modena, Italy
Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy

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Stefano Landi Department of Biology, University of Pisa, Pisa, Italy

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Livio Casarini Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy

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To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.

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M Grussendorf Department of Internal Medicine, University Hospital, Düsseldorf, Germany

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I Ruschenburg MVZ Wagnerstibbe Center for Cytology and Pathology, Einbeck, Germany

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G Brabant Department of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, UK

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Objectives

Ultrasound diagnosis of thyroid nodules has greatly increased their detection rate. Their risk for malignancy is estimated between 7 and 15% in data from specialized centers which are used for guidelines recommendations. This high rate causes considerable anxiety to patients upon first diagnosis. Here, we retrospectively analyzed the malignancy rate of sonographically diagnosed nodules larger than 1 cm from a primary/secondary care center when long-term longitudinal follow-up was included.

Patients/methods

In the study, 17,592 patients were diagnosed with a thyroid nodule larger than 1 cm, of whom 7776 were assessed by fine-needle aspiration cytology (FNAC) and 9816 by sonography alone. 9568 patients were initially discharged due to innocent results of FNAC and/or ultrasound. In 1904 patients, definitive histology was obtained, and 6731 cases were included in the long-term follow-up (up to 23 years, median 5 years).

Results

Malignancy was histologically confirmed in 189 patients (1.1% of all) when excluding accidentally diagnosed papillary microcarcinomas. 155 were diagnosed during the first year of management, 25 in years 2–5 of follow-up, 9 in years 6–10 and nil in 1165 patients followed beyond 10 years.

Conclusions

The malignancy rate of thyroid nodules from primary/secondary care was much lower than that previously reported. During follow-up for more than 5 years, their rate rapidly dropped to less than 1/1000 cases. This low malignancy rate may help to reassure patients first confronted with the diagnosis of a thyroid nodule, substantially reduce their anxiety and avoid unwarranted diagnostic and therapeutic procedures.

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Diana Borges Duarte Division of Endocrinology, Centro Hospitalar e Universitário do Porto, Porto, Portugal

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Vânia Benido Silva Division of Endocrinology, Centro Hospitalar e Universitário do Porto, Porto, Portugal

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Guilherme Assunção Division of Endocrinology, Centro Hospitalar e Universitário do Porto, Porto, Portugal

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André Couto Carvalho Division of Endocrinology, Centro Hospitalar e Universitário do Porto, Porto, Portugal

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Cláudia Freitas Division of Endocrinology, Centro Hospitalar e Universitário do Porto, Porto, Portugal

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Introduction

The occurrence of non-thyroidal second primary malignancy (NTSPM) in patients with papillary thyroid cancer (PTC) is well documented, but epidemiological data are conflicting.

Objective

The aim of this study was to evaluate the incidence of NTSPM in a large series of patients with PTC and to assess its potential risk factors.

Methods

Single-center cohort study with retrospective data collection conducted on consecutive PTC patients diagnosed from 1988 to 2018 with a minimum follow-up time of 2 years. NTSPM was defined as any primary malignancy with histological confirmation occurring in an anatomical site other than the thyroid. According to the timing of occurrence, NTSPM were subdivided into anachronous, synchronous or metachronous (diagnosed >6 months before, within 6 months and >6 months after PTC diagnosis, respectively).

Results

We included 773 individuals (83.3% females), median age at PTC diagnosis was 47.0 (IQR: 37.0–58.0) years and median follow-up time was 9.9 (6.2–16.3) years. Incidence of NTSPM was 15.5% (n  = 120) and its standard incidence ratio (SIR) was higher when compared to the general population (SIR: 2.70). Family history of malignancy and younger age at diagnosis were associated respectively with 206 and 4% increased risk of developing metachronous neoplasia (HR: 2.06 (95% CI: 1.10–3.86) and 1.04 (95% CI: 1.02–1.05), respectively).

Conclusion

In our series, the occurrence of NTSPM was not uncommon and its incidence was higher compared to the general population. First-degree family history of malignancy was a strong risk factor for multiple primary malignancies.

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Ian D Hay Department of Medicine 1, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

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Suneetha Kaggal Department of Health Sciences Research, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

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Geoffrey B Thompson Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

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Objective

To determine whether radioiodine remnant ablation (RRA) reduces cause-specific mortality (CSM) or tumor recurrence rates (TRR) after potentially curative bilateral thyroidectomy (BT) in low-risk adult papillary thyroid carcinoma (APTC) patients, we compared postoperative outcomes in 1836 pTNM stage I APTC patients having BT alone with 832 having BT+RRA during two consecutive 25-year periods.

Methods

The THEN cohort (consecutively managed during 1966–1990) comprised 809 patients (36% having BT+RRA) and the NOW cohort (1991–2015) comprised 1859 patients (29% BT+RRA). Analyses of differences in occurrence rates between BT alone and BT+RRA patients were performed with SAS software.

Results

During 1966–1990, when RRA rates rose ten-fold, 20-year CSM after BT alone was 0.6% and after BT+RRA was 1.2% (P = 0.66); during 1991–2015, when RRA rates progressively fell, no PTC deaths occurred in 1859 patients. In the THEN cohort, RRA did not significantly improve TRR at local, regional, or distant sites (P > 0.1), when compared to BT alone. RRA in NOW cohort was administered to 49% of node-positive (pN1) patients and 17% of node-negative (pN0/NX) patients (P < 0.0001); TRR therefore, were examined separately for pN0/NX and pN1 patients. In 1157 pN0/NX cases, 20-year locoregional TRR were 3.1% after BT and were higher (P = 0.049) at 8.6% after BT+RRA. In four pN1 groups, stratified by metastatic nodal burden, RRA did not significantly reduce the locoregional TRR observed after BT with curative intent (P > 0.5).

Conclusions

In a 5-decade experience, RRA administered postoperatively to stage I APTC patients did not reduce either CSM or TRR and should probably not be indicated when such patients undergo potentially curative BT.

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Jan Jiskra 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Jiří Horáček 4th Department of Medicine, Faculty of Medicine, Charles University, University Hospital Hradec Králové, Czech Republic

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Sylvie Špitálníková Department of Nuclear Medicine, District Hospital, Havlíčkův Brod, Czech Republic

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Jan Paleček 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Zdeňka Límanová 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Jan Krátký 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Drahomíra Springer Department of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Kristýna Žabková 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Hana Vítková 3rd Department of Medicine, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

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Objective

Thyroid nodules are a common finding in the general population. The primary aim of the study was to determine the prevalence of thyroid nodules and cancer found by ultrasound (US) in women who underwent screening for thyroid dysfunction during pregnancy.

Design

A double-centric, retrospective, cohort study.

Patients and methods

We searched through medical records, including thyroid ultrasonography, of pregnant women who were positively screened for thyroid disorders (using thyroid-stimulating hormone and thyroid antibodies) from an unselected population (‘universal screening group’, n  = 690) and of women who underwent the testing based on the presence of clinical risk factors defined by American Thyroid Association (’case-finding group’, n  = 249).

Results

Prevalence of benign and malignant thyroid nodules was lower in the ‘universal screening group’ than in the ‘case-finding group’ (9.9% vs 17.7%, P= 0.002, and 0.9% vs 7.2%, P< 0.001, respectively). Consistently, the thyroid cancer rate was lower among the nodules in the ‘universal screening group’ than in the ‘case-finding group’ (8.1% vs 29.0%, P= 0.003). Ultrasound EU-TIRADS (European Thyroid Imaging and Reporting Data System) category ≥4 had a 95.8% sensitivity for thyroid cancer. In palpable nodules, the prevalence of cancer was significantly higher than in the non-palpable ones (44.0% vs 2.2%, P < 0.001). In a multivariate regression analysis, thyroid nodules were associated with a history of infertility and parity.

Conclusions

Compared to the data from cancer registries, universal screening allowed detecting thyroid cancer in pregnancy three to five times more frequently, but the cancer rate among nodules (8.1%) did not differ from the common population. US had very good sensitivity for thyroid cancer in pregnancy.

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Sara Donato Endocrinology Department, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal

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Helder Simões Endocrinology Department, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal
NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

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Valeriano Leite Endocrinology Department, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal
NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal

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Introduction: Struma ovarii (SO) is a rare ovarian teratoma characterized by the presence of thyroid tissue in more than 50% of the tumor. Malignant transformation is rare and the most common associated malignancy is papillary thyroid carcinoma (PTC). Pregnancy may represent a stimulus to differentiated thyroid cancer (DTC) growth in patients with known structural or biochemical evidence of disease, but data about malignant SO evolution during pregnancy are rare. We present the first reported case of a pregnant patient with malignant SO and biochemical evidence of disease. Case Presentation: A previously healthy 35-year-old female diagnosed with a suspicious left pelvic mass on routine ultrasound was submitted to laparoscopic oophorectomy which revealed a malignant SO with areas of PTC. A 15-mm thyroid nodule (Bethesda V in the fine-needle aspiration cytology) was detected by palpation and total thyroidectomy was performed. Histology revealed a 15 mm follicular variant of PTC (T1bNxMx). Subsequently, she received 100 mCi of radioactive iodine therapy (RAIT) with the whole-body scan showing only moderate neck uptake. Her suppressed thyroglobulin (Tg) before RAI was 1.1 ng/mL. She maintained biochemical evidence of disease, with serum Tg levels of 7.6 ng/mL. She got pregnant 14 months after RAIT, and during pregnancy, Tg increased to 21.5 ng/mL. After delivery, Tg decreased to 14 ng/mL but, 6 months later, rose again and reached 31.9 ng/mL on the last follow-up visit. TSH was always suppressed during follow-up. At the time of SO diagnosis, a chest computed tomography scan showed 4 bilateral lung micronodules in the upper lobes which were nonspecific, and 9 months after diagnosis, a pelvic MRI revealed a suspicious cystic nodule located on the oophorectomy bed. These lung and pelvic nodules remained stable during follow-up. Neck ultrasonography, abdominal MRI, and fluorodeoxyglucose-positron emission tomography showed no suspicious lesions. Discussion/Conclusion: As for DTC, pregnancy seems to represent a stimulus to malignant SO growth. This can be caused by the high levels of estrogen during pregnancy that may bind to receptors in malignant cells and/or by the high levels of hCG which is known to stimulate TSH receptors.

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Ayanthi Wijewardene Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Matti Gild Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Carolina Nylén Endocrine Surgery Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Geoffrey Schembri Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Nuclear Medicine Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Paul Roach Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Nuclear Medicine Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Jeremy Hoang Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Nuclear Medicine Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Ahmad Aniss Endocrine Surgery Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Anthony Glover Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Endocrine Surgery Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Mark Sywak Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Endocrine Surgery Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Stan Sidhu Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
Endocrine Surgery Department, Royal North Shore Hospital, Sydney, New South Wales, Australia

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Diana Learoyd Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Bruce Robinson Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Lyndal Tacon Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Roderick Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Objective: Our study aimed to analyse temporal trends in radioactive iodine (RAI) treatment for thyroid cancer over the past decade; to analyse key factors associated with clinical decisions in RAI dosing; and to confirm lower activities of RAI for low-risk patients were not associated with an increased risk of recurrence. Methods: Retrospective analysis of 1,323 patients who received RAI at a quaternary centre in Australia between 2008 and 2018 was performed. Prospectively collected data included age, gender, histology, and American Joint Committee on Cancer stage (7th ed). American Thyroid Association risk was calculated retrospectively. Results: The median activities of RAI administered to low-risk patients decreased from 3.85 GBq (104 mCi) in 2008–2016 to 2.0 GBq (54 mCi) in 2017–2018. The principal driver of this change was an increased use of 1 GBq (27 mCi) from 1.3% of prescriptions in 2008–2011 to 18.5% in 2017–2018. In patients assigned as low risk per ATA stratification, lower activities of 1 GBq or 2 GBq (27 mCi or 54 mCi) were not associated with an increased risk of recurrence. In patients assigned to intermediate- or high-risk categories who received RAI as adjuvant therapy, there was no difference in risk of recurrence between 4 GBq (108 mCi) and 6 GBq (162 mCi). Conclusions: Our data demonstrate an evolution of RAI activities consistent with translation of ATA guidelines into clinical practice. Use of lower RAI activities was not associated with an increase in recurrence in low-risk thyroid cancer patients. Our data also suggest lower RAI activities may be as efficacious for adjuvant therapy in intermediate- and high-risk patients.

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Yuwei Liu Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Shengcai Wang Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Yanzhen Li Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Xuexi Zhang Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Zhiyong Liu Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Qiaoyin Liu Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Nian Sun Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Jie Zhang Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Wentong Ge Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Yongli Guo Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Yuanhu Liu Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Xiaolian Fang Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Tingting Ji Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Jun Tai Children’s Hospital Capital Institute of Pediatrics, Department of Otolaryngology, Head and Neck Surgery, Beijing, China

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Xin Ni Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

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Objectives: The objectives of this study were to explore the clinical heterogeneity of differentiated thyroid cancer (DTC) between prepubertal children and adolescents and guide clinical treatment. Methods: A retrospective study included patients with DTC aged ≤19 years in Beijing Children’s Hospital from June 2014 to June 2019. All patients were enrolled and divided into 2 subgroups based on the threshold age of 10 years, namely the childhood group (CG) (≤10 years old); and the adolescent group (AG) (between 10 and 19 years old). The χ<sup>2</sup> test and Fisher’s exact test were used to estimate the effect of risk factors in the 2 age groups. Multivariate binary logistic regression models were conducted to assess the recurrent risk factors. Results: Seventy cases of DTC were included with an average age of 9.94 ± 2.88 years, including 35 in CG and 35 in AG. The most common clinical manifestation was a painless mass in the neck, accounting for 77.1% (54/70) of patients. Compared with the AG, the CG was more likely to have lymph node metastasis (p = 0.022) and distant metastasis (p = 0.041). The CG was more likely to have extrathyroidal extension (p = 0.012) and had a significantly higher recurrence rate than the AG (p = 0.040). Age was an independent variable predictive of recurrence (p = 0.0347). Conclusion: Regional invasiveness, cervical lymph node metastasis, and distant metastasis of DTC were more likely to occur in children ≤10 years old. Meanwhile, children ≤10 years old with DTC were more likely to have recurrence than adolescent’s postsurgical treatment. Thus, children younger than 10 years of age with DTC should be treated more aggressively.

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Shinsuke Shinkai Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Kenji Ohba Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
Medical Education Center, Hamamatsu University School of Medicine, Shizuoka, Japan

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Kennichi Kakudo Department of Pathology and Thyroid Disease Center, Izumi City General Hospital, Osaka, Japan

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Takayuki Iwaki Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan

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Yoshihiro Mimura Department of Internal Medicine, American Hospital of Paris, Neuilly sur Seine, France

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Akio Matsushita Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Go Kuroda Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Yuki Sakai Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Nobuhiko Nishino Department of Surgery, Maruyama Hospital, Shizuoka, Japan

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Kazuo Umemura Medical Education Center, Hamamatsu University School of Medicine, Shizuoka, Japan
Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan

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Takafumi Suda Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Shigekazu Sasaki Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

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Introduction: Hyperfunctioning papillary thyroid carcinoma (PTC) is rare and consequently, little information on its molecular etiology is available. Although BRAF V600E (BRAF c.1799T>A, p.V600E) is a prominent oncogene in PTC, its mutation has not yet been reported in hyperfunctioning PTC. Case Presentation: Ultrasonography detected a 26-mm nodule in the right lobe of the thyroid gland of a 48-year-old man. Thyroid function tests indicated that he was hyperthyroid with a TSH level of 0.01 mIU/L (reference range: 0.05–5.00) and a free thyroxine level of 23.2 pmol/L (reference range: 11.6–21.9). TSHR autoantibodies were <0.8 IU/L (reference value: <2.0 IU/L). The <sup>99m</sup>Tc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with a decreased uptake in the remainder of the gland. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignancy. The histopathological diagnosis was conventional PTC. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 1–10), GNAS (exons 7–10), EZH1 (exon 16), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) identified a heterozygous point mutation in BRAF V600E in a tumor tissue sample. In addition, we identified a TSHR D727E polymorphism (TSHR c.2181C>G, p.D727E) in both the tumor and the surrounding normal thyroid tissue. Discussion and Conclusions: We report a case of hyperfunctioning PTC with a BRAF V600E mutation for the first time. Our literature search yielded 16 cases of hyperfunctioning thyroid carcinoma in which a mutational analysis was conducted. We identified TSHR mutations in 13 of these cases. One case revealed a combination of TSHR and KRAS mutations; the other case revealed a TSHR mutation with a PAX8/PPARG rearrangement. These findings suggest that the concomitant activation of oncogenes (in addition to constitutive activation of the TSHR-cyclic AMP cascade) are associated with the malignant phenotype in hyperfunctioning thyroid nodules.

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Alexander Gorshtein Endocrine Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Ilana Slutzky-Shraga Endocrine Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Eyal Robenshtok Endocrine Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Carlos Benbassat Endocrine Institute, Shamir Medical Center (Formerly Assaf Harofeh Medical Center), Beer Yaakov, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Dania Hirsch Endocrine Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Objective: Outcomes of patients with cytologically indeterminate thyroid nodules not referred for thyroidectomy have hardly been investigated. We previously reported outcomes of 322 patients with thyroid nodules classified according to the Bethesda System of Reporting Thyroid Cytology (BSRTC) as indeterminate (B3/B4), of whom 123 (38.2%) underwent thyroidectomy. In the present extension study, we investigated adherence and outcomes in the remaining unoperated 199 patients. Methods: We conducted a file review of 189/199 patients with thyroid nodules cytologically diagnosed as B3 (n = 174) or B4 (n = 15) in 2011–2012 who were conservatively followed at our institution until 2019. Results: Among 174 patients with B3 nodules, 140 (80.4%) underwent repeated ultrasound. Nodular growth was detected in 23 (16.4%), and findings remained stable in 105 (75%). Fine-needle aspiration was repeated in 88/174 patients (50.6%), with B2 results in 62 (70.4%) and B3/B4/B5 in 20 (22.7%). Thyroidectomy was performed in 14/174 patients (8%) in the B3 and 5/15 patients (33%) in the B4 group at a median of 5 years’ follow-up; thyroid cancer was diagnosed in 4/14 patients (28.5%) and 3/5 patients (60%), respectively. For B3 patients who remained unoperated, none had evidence of thyroid cancer at last follow-up. A reason for avoiding surgery was documented in 6/10 unoperated B4 patients (1 thyroid lymphoma, 3 died of unrelated causes, 2 were considered inoperable due to advanced age). Conclusions: Most patients with initially unoperated B3/B4 nodules adhere, at least partially, to active surveillance. For B3 nodules, subsequent thyroidectomy and thyroid cancer detection are rare events, and patients may be safely managed without using molecular markers. Thyroid cancer is diagnosed in most B4 patients who undergo thyroidectomy in our institution.

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