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Thyroid Nodule

  • Markus Eszlinger
  • Laszlo Hegedüs
  • Ralf Paschke
Reference work entry
Part of the Endocrinology book series (ENDOCR)

Abstract

Benign thyroid nodules are highly prevalent in iodine-deficient areas. Histologically, benign thyroid nodules are characterized by morphologic criteria as encapsulated lesions (true adenomas) or adenomatous nodules, which lack a capsule. On functional grounds, nodules are classified as either “cold,” “normal,” or “hot,” depending on whether they show decreased, normal, or increased uptake on scintiscan. Approximately 50–85% of all nodules are “cold,” up to 40% are scintigraphically indifferent and about 10% are “hot,” although the prevalence will vary geographically with the ambient iodine supply and with the clinical setting.

Hot thyroid nodules (autonomously functioning thyroid nodules, AFTNs) are mainly due to mutations which confer a constitutive activation of the cAMP cascade (e.g., TSHR and Gsα mutations) which results in a stimulation of growth and function. In contrast, the molecular etiology of cold thyroid nodules (CTNs) is still largely unknown.

Thyroid autonomy (i.e., AFTNs) is an almost exclusively benign disease, and there is little evidence in the literature to suggest the contrary. In contrast, the differential diagnosis of scintigraphically indifferent and CTNs includes benign follicular adenoma and adenomatous nodules, as well as papillary thyroid carcinoma and its variants and follicular thyroid carcinoma. While fine-needle aspiration cytology is currently the most sensitive and specific tool to select thyroid nodules for surgery after prioritization by assessment of ultrasound malignancy criteria, it is characterized by an inherent limitation, resulting in “indeterminate” cytologies. Molecular tests in the form of “rule out” and “rule in” malignancy tests have been proposed to fill this diagnostic gap.

The most important therapeutic options for hot nodules are radioiodine therapy or surgery and surgery for scintigraphically indifferent and CTNs if symptomatic or associated with increased malignancy risk.

Keywords

Autonomously functioning thyroid nodules Cold thyroid nodules Mutations Ultrasonography Scintigraphy Fine-needle aspiration cytology Molecular diagnostics Antithyroid drug treatment Surgery Radioiodine therapy Thyroid hormone treatment Percutaneous interventional therapy 

References

  1. Abrahamsen B, Jorgensen HL, Laulund AS, Nybo M, Brix TH, Hegedus L. Low serum thyrotropin level and duration of suppression as a predictor of major osteoporotic fractures-the OPENTHYRO register cohort. J Bone Miner Res. 2014;29(9):2040–50.CrossRefPubMedGoogle Scholar
  2. Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):705–15.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Alexander EK, Schorr M, Klopper J, et al. Multicenter clinical experience with the afirma gene expression classifier. J Clin Endocrinol Metab. 2014;99(1):119–25.PubMedCrossRefPubMedCentralGoogle Scholar
  4. al-Suliman NN, Ryttov NF, Qvist N, Blichert-Toft M, Graversen HP. Experience in a specialist thyroid surgery unit: a demographic study, surgical complications, and outcome. Eur J Surg. 1997;163(1):13–20.PubMedPubMedCentralGoogle Scholar
  5. An JH, Song KH, Kim SK, et al. RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma. Clin Endocrinol. 2015;82(5):760–6.CrossRefGoogle Scholar
  6. Aragon HP, Olson MT, Fazeli R, et al. The impact of molecular testing on the surgical management of patients with thyroid nodules. Ann Surg Oncol. 2014;21(6):1862–9.CrossRefGoogle Scholar
  7. Armstrong MJ, Yang H, Yip L, et al. PAX8/PPARgamma rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. Thyroid. 2014;24(9):1369–74.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bahre M, Hilgers R, Lindemann C, Emrich D. Thyroid autonomy: sensitive detection in vivo and estimation of its functional relevance using quantified high-resolution scintigraphy. Acta Endocrinol. 1988;117(2):145–53.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Baloch ZW, Seethala RR, Faquin WC et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a changing paradigm in thyroid surgical pathology and implications for thyroid cytopathology. Cancer Cytopathol. 2016.Google Scholar
  10. Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000;10(1):19–23.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Beaudenon-Huibregtse S, Alexander EK, Guttler RB, et al. Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid. 2014;24(10):1479–87.PubMedCrossRefPubMedCentralGoogle Scholar
  12. Belfiore A, La Rosa GL, La Porta GA, et al. Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity. Am J Med. 1992;93:363–9.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bennedbaek FN, Hegedus L. Management of the solitary thyroid nodule: results of a North American survey. J Clin Endocrinol Metab. 2000;85(7):2493–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Bennedbaek FN, Hegedus L. Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab. 2003;88(12):5773–7.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Bennedbaek FN, Karstrup S, Hegedus L. Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol. 1997;136(3):240–50.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Bennedbaek FN, Perrild H, Hegedus L. Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey. Clin Endocrinol. 1999;50(3):357–63.CrossRefGoogle Scholar
  17. Berghout A, Wiersinga WM, Smits NJ, Touber JL. Interrelationships between age, thyroid volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter. Am J Med. 1990;89(5):602–8.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Bol S, Belge G, Thode B, Bartnitzke S, Bullerdiek J. Structural abnormalities of chromosome 2 in benign thyroid tumors. Three new cases and review of the literature. Cancer Genet Cytogenet. 1999;114(1):75–7.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. Acta Cytol. 2012;56(4):333–9.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Bonnema SJ, Hegedus L. Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome. Endocr Rev. 2012;33(6):920–80.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bonnema SJ, Bennedbaek FN, Wiersinga WM, Hegedus L. Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol. 2000;53(1):5–12.CrossRefGoogle Scholar
  22. Bonnema SJ, Bennedbaek FN, Ladenson PW, Hegedus L. Management of the nontoxic multinodular goiter: a North American survey. J Clin Endocrinol Metab. 2002;87(1):112–7.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Brandt F, Almind D, Christensen K, Green A, Brix TH, Hegedus L. Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a danish nationwide register-based cohort study of twins and singletons. J Clin Endocrinol Metab. 2012;97(11):4123–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Caillou B, Dupuy C, Lacroix L, et al. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX, Duox) genes and proteins in human thyroid tissues. J Clin Endocrinol Metab. 2001;86(7):3351–8.PubMedPubMedCentralGoogle Scholar
  25. Calebiro D, Grassi ES, Eszlinger M, et al. Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. J Clin Invest. 2016;126(9):3383–8.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Campenni A, Giovanella L, Siracusa M, et al. (99m)Tc-methoxy-isobutyl-isonitrile scintigraphy is a useful tool for assessing the risk of malignancy in thyroid nodules with indeterminate fine-needle cytology. Thyroid. 2016;26(8):1101–9.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90.CrossRefGoogle Scholar
  28. Cantara S, Capezzone M, Marchisotta S, et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab. 2010;95(3):1365–9.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J. Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues. Diagn Mol Pathol. 1996;5(1):45–52.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Ceccarelli C, Bencivelli W, Vitti P, Grasso L, Pinchera A. Outcome of radioiodine-131 therapy in hyperfunctioning thyroid nodules: a 20 years’ retrospective study. Clin Endocrinol. 2005;62(3):331–5.CrossRefGoogle Scholar
  31. Chan JKC, Hirokawa M, et al. Tumours of the thyroid and parathyroid: follicular adenoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. WHO classification of tumours: pathology & genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. p. 98–103.Google Scholar
  32. Cheung L, Messina M, Gill A, et al. Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab. 2003;88(1):354–7.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Chiovato L, Mariotti S, Pinchera A. Thyroid diseases in the elderly. Bailliere Clin Endocrinol Metab. 1997;11(2):251–70.CrossRefGoogle Scholar
  34. Chudova D, Wilde JI, Wang ET, et al. Molecular classification of thyroid nodules using high-dimensionality genomic data. J Clin Endocrinol Metab. 2010;95(12):5296–304.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2009;132(5):658–65.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Cibas ES, Baloch ZW, Fellegara G, et al. A prospective assessment defining the limitations of thyroid nodule pathologic evaluation. Ann Intern Med. 2013;159(5):325–32.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352(9):905–17.PubMedCrossRefPubMedCentralGoogle Scholar
  38. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109–42.PubMedCrossRefPubMedCentralGoogle Scholar
  39. de Vijlder JJ. Primary congenital hypothyroidism: defects in iodine pathways. Eur J Endocrinol. 2003;149(4):247–56.PubMedCrossRefPubMedCentralGoogle Scholar
  40. Deleu S, Allory Y, Radulescu A, et al. Characterization of autonomous thyroid adenoma: metabolism, gene expression, and pathology. Thyroid. 2000;10(2):131–40. 2000; 10(2):131-140.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Demirel K, Kapucu O, Yucel C, Ozdemir H, Ayvaz G, Taneri F. A comparison of radionuclide thyroid angiography, (99m)Tc-MIBI scintigraphy and power Doppler ultrasonography in the differential diagnosis of solitary cold thyroid nodules. Eur J Nucl Med Mol Imaging. 2003;30(5):642–50.PubMedCrossRefPubMedCentralGoogle Scholar
  42. Depoortere F, Pirson I, Bartek J, Dumont JE, Roger PP. Transforming growth factor beta(1) selectively inhibits the cyclic AMP-dependent proliferation of primary thyroid epithelial cells by preventing the association of cyclin D3-cdk4 with nuclear p27(kip1). Mol Biol Cell. 2000;11(3):1061–76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Derwahl M, Studer H. Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts. Exp Clin Endocrinol Diabetes. 2001;109(5):250–60.PubMedCrossRefPubMedCentralGoogle Scholar
  44. Dohan O, Baloch Z, Banrevi Z, LiVolsi V, Carrasco N. Rapid communication: predominant intracellular overexpression of the Na(+)/I(−) symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab. 2001;86(6):2697–700.PubMedPubMedCentralGoogle Scholar
  45. Dohan O, De la Vieja, Paroder V, et al. The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003;24(1):48–77.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules – a randomised study. Eur J Endocrinol. 2005;152(3):341–5.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Dossing H, Bennedbaek FN, Hegedus L. Long-term outcome following interstitial laser photocoagulation of benign cold thyroid nodules. Eur J Endocrinol. 2011;165(1):123–8.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Dossing H, Bennedbaek FN, Hegedus L. Interstitial laser photocoagulation (ILP) of benign cystic thyroid nodules – a prospective randomized trial. J Clin Endocrinol Metab. 2013;98(7):E1213–7.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Dugrillon A, Bechtner G, Uedelhoven WM, Weber PC, Gärtner R. Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3′,5′-monophosphate formation. Endocrinology. 1990;127(1):337–43.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Dunn JT, Dunn AD. Update on intrathyroidal iodine metabolism. Thyroid. 2001;11(5):407–14.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Eggo MC, Bachrach LK, Burrow GN. Interaction of TSH, insulin and insulin-like growth factors in regulating thyroid growth and function. Growth Factors. 1990;2(2–3):99–109.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid. 1998;8(4):277–82.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol. 1999;50(4):529–35.CrossRefGoogle Scholar
  54. Eszlinger M, Paschke R. Molecular fine-needle aspiration biopsy diagnosis of thyroid nodules by tumor specific mutations and gene expression patterns. Mol Cell Endocrinol. 2010;322(1–2):29–37.PubMedCrossRefPubMedCentralGoogle Scholar
  55. Eszlinger M, Krohn K, Frenzel R, Kropf S, Tonjes A, Paschke R. Gene expression analysis reveals evidence for inactivation of the TGF-beta signaling cascade in autonomously functioning thyroid nodules. Oncogene. 2004;23(3):795–804.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Eszlinger M, Krohn K, Berger K, et al. Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules. J Clin Endocrinol Metab. 2005;90(2):1163–70.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Eszlinger M, Krogdahl A, Munz S, et al. Impact of molecular screening for point mutations and rearrangements in routine air-dried fine-needle aspiration samples of thyroid nodules. Thyroid. 2014;24(2):305–13.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Eszlinger M, Piana S, Moll A, et al. Molecular testing of thyroid fine needle aspirations (FNA) improves pre-surgical diagnosis and supports the histological identification of minimally invasive follicular thyroid carcinomas. Thyroid. 2015;25(4):401–9.PubMedCrossRefPubMedCentralGoogle Scholar
  59. Eszlinger M, Lau L, Ghaznavi S, Symonds C, Chandarana SP, Khalil M, Paschke R. Molecular profiling of thyroid nodule fine-needle aspiration cytology. Nat Rev Endocrinol. 2017a.  https://doi.org/10.1038/nrendo.2017.24.
  60. Eszlinger M, Böhme K, Ullmann M, et al. Evaluation of a two-year routine application of molecular testing of thyroid fine needle aspirations (FNA) using a 7-gene panel in a primary refferral setting in Germany. Thyroid. 2017b.  https://doi.org/10.1089/thy.2016.0445.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Fagin JA. Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid. Mol Endocrinol. 2002;16(5):903–11.PubMedPubMedCentralGoogle Scholar
  62. Faquin WC, Wong LQ, Afrogheh AH, et al. Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology. Cancer Cytopathol. 2016;124(3):181–7.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Farahati J, Demidchik EP, Biko J, Reiners C. Inverse association between age at the time of radiation exposure and extent of disease in cases of radiation-induced childhood thyroid carcinoma in Belarus. Cancer. 2000;88(6):1470–6.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Fassina AS, Montesco MC, Ninfo V, Denti P, Masarotto G. Histological evaluation of thyroid carcinomas: reproducibility of the “WHO” classification. Tumori. 1993;79(5):314–20.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Fast S, Bonnema SJ, Hegedus L. The majority of Danish nontoxic goitre patients are ineligible for Levothyroxine suppressive therapy. Clin Endocrinol. 2008;69(4):653–8.CrossRefGoogle Scholar
  66. Ferrari C, Reschini E, Paracchi A. Treatment of the autonomous thyroid nodule: a review. Eur J Endocrinol. 1996;135(4):383–90.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Ferraz C, Eszlinger M, Paschke R. Current state and future perspective of molecular diagnosis of fine-needle aspiration biopsy of thyroid nodules. J Clin Endocrinol Metab. 2011;96(7):2016–26.PubMedCrossRefPubMedCentralGoogle Scholar
  68. Ferraz C, Rehfeld C, Krogdahl A, et al. Detection of PAX8/PPARG and RET/PTC rearrangements is feasible in routine air-dried fine needle aspiration smears. Thyroid. 2012;22(10):1025–30.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Franc B, de la Salmoniere P, Lange F, et al. Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol. 2003;34(11):1092–100.PubMedCrossRefPubMedCentralGoogle Scholar
  70. Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle P. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet. 1999;353(9170):2111–5.PubMedCrossRefPubMedCentralGoogle Scholar
  71. Fuhrer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab. 1997;82(11):3885–91.PubMedPubMedCentralGoogle Scholar
  72. Fukahori M, Yoshida A, Hayashi H, et al. The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid. 2012;22(7):683–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Garcia-Delgado M, Gonzalez-Navarro CJ, Napal MC, Baldonado C, Vizmanos JL, Gullon A. Higher sensitivity of denaturing gradient gel electrophoresis than sequencing in the detection of mutations in DNA from tumor samples. Biotechniques. 1998;24(1):72. 74, 76.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Garcia-Rostan G, Zhao H, Camp RL, et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol. 2003;21(17):3226–35.PubMedCrossRefPubMedCentralGoogle Scholar
  75. Gärtner R, Schopohl D, Schaefer S, et al. Regulation of transforming growth factor beta 1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine, or delta-iodolactone. Thyroid. 1997;7(4):633–40.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Gemsenjager E. The surgical treatment of autonomous nodular goiter. Prospective long-term study. Schweiz Med Wochenschr. 1992;122(18):687–92.PubMedPubMedCentralGoogle Scholar
  77. Georgopoulos NA, Sykiotis GP, Sgourou A, et al. Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway. Eur J Endocrinol. 2003;149(4):287–92.PubMedCrossRefPubMedCentralGoogle Scholar
  78. Gharib H, Hegedus L, Pacella CM, Baek JH, Papini E. Clinical review: nonsurgical, image-guided, minimally invasive therapy for thyroid nodules. J Clin Endocrinol Metab. 2013;98(10):3949–57.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Gharib H, Papini E, Garber JR, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract. 2016;22(5):622–39.PubMedPubMedCentralGoogle Scholar
  80. Gozu HI, Bircan R, Krohn K, et al. Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol. 2006;155(4):535–45.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Grubeck-Loebenstein B, Buchan G, Sadeghi R, et al. Transforming growth factor beta regulates thyroid growth. Role in the pathogenesis of nontoxic goiter. J Clin Invest. 1989;83(3):764–70.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Grussendorf M, Reiners C, Paschke R, Wegscheider K. Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2011;96(9):2786–95.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Hall P, Boice Jr JD, Berg G, et al. Leukaemia incidence after iodine-131 exposure. Lancet. 1992;340(8810):1–4.PubMedCrossRefPubMedCentralGoogle Scholar
  84. Hamburger JI. Evolution of toxicity in solitary nontoxic autonomously functioning thyroid nodules. J Clin Endocrinol Metab. 1980;50(6):1089–93.PubMedCrossRefPubMedCentralGoogle Scholar
  85. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Hedinger C. Histological typing of thyroid tumors. Berlin: Springer Verlag; 1988.CrossRefGoogle Scholar
  87. Hegedus L. Thyroid ultrasound. Endocrinol Metab Clin N Am. 2001;30(2):339–ix.CrossRefGoogle Scholar
  88. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351(17):1764–71.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Hegedus L. Can elastography stretch our understanding of thyroid histomorphology? J Clin Endocrinol Metab. 2010;95(12):5213–5.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Hegedus L, Nygaard B, Hansen JM. Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab. 1999;84(2):756–60.PubMedPubMedCentralGoogle Scholar
  91. Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev. 2003;24(1):102–32.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med. 1998;338(20):1438–47.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Ho AS, Sarti EE, Jain KS, et al. Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS). Thyroid: Off J Am Thyroid Assoc. 2014;24(5):832–9.CrossRefGoogle Scholar
  94. Holm LE, Hall P, Wiklund K, et al. Cancer risk after iodine-131 therapy for hyperthyroidism. J Natl Cancer Inst. 1991;83(15):1072–7.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Howitt BE, Jia Y, Sholl LM, Barletta JA. Molecular alterations in partially-encapsulated or well-circumscribed follicular variant of papillary thyroid carcinoma. Thyroid. 2013;23(10):1256–62.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Ito Y, Uruno T, Nakano K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid. 2003;13(4):381–7.PubMedCrossRefPubMedCentralGoogle Scholar
  97. Jaeschke H, Mueller S, Eszlinger M, Paschke R. Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas. Clin Endocrinol. 2010;73(6):815–20.CrossRefGoogle Scholar
  98. Jang EK, Song DE, Sim SY, et al. NRAS codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma. Thyroid. 2014;24(8):1275–81.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Jarlov AE, Nygaard B, Hegedus L, Hartling SG, Hansen JM. Observer variation in the clinical and laboratory evaluation of patients with thyroid dysfunction and goiter. Thyroid. 1998;8(5):393–8.PubMedCrossRefPubMedCentralGoogle Scholar
  100. Kim CS, Zhu X. Lessons from mouse models of thyroid cancer. Thyroid. 2009;19(12):1317–31.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE, Roger PP. Regulation of thyroid cell proliferation by tsh and other factors: a critical evaluation of in vitro models. Endocr Rev. 2001;22(5):631–56.PubMedCrossRefPubMedCentralGoogle Scholar
  102. Knudsen N, Perrild H, Christiansen E, Rasmussen S, Dige-Petersen H, Jorgensen T. Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency. Eur J Endocrinol. 2000;142(3):224–30.PubMedCrossRefPubMedCentralGoogle Scholar
  103. Krane JF, Cibas ES, Alexander EK, Paschke R, Eszlinger M. Molecular analysis of residual ThinPrep material from thyroid FNAs increases diagnostic sensitivity. Cancer Cytopathol. 2015;123(6):356–61.PubMedCrossRefPubMedCentralGoogle Scholar
  104. Krohn K, Paschke R. Progress in understanding the etiology of thyroid autonomy. J Clin Endocrinol Metab. 2001a;86(7):3336–45.PubMedPubMedCentralGoogle Scholar
  105. Krohn K, Paschke R. Loss of heterozygocity at the thyroid peroxidase gene locus in solitary cold thyroid nodules. Thyroid. 2001b;11(8):741–7.PubMedCrossRefPubMedCentralGoogle Scholar
  106. Krohn K, Paschke R. BRAF mutations are not an alternative explanation for the molecular etiology of ras-mutation negative cold thyroid nodules. Thyroid. 2004;14(5):359–61.PubMedCrossRefPubMedCentralGoogle Scholar
  107. Krohn K, Emmrich P, Ott N, Paschke R. Increased thyroid epithelial cell proliferation in toxic thyroid nodules. Thyroid. 1999;9(3):241–6.PubMedCrossRefPubMedCentralGoogle Scholar
  108. Krohn K, Wohlgemuth S, Gerber H, Paschke R. Hot microscopic areas of iodine-deficient euthyroid goitres contain constitutively activating TSH receptor mutations [In Process Citation]. J Pathol. 2000;192(1):37–42.PubMedCrossRefPubMedCentralGoogle Scholar
  109. Krohn K, Reske A, Ackermann F, Muller A, Paschke R. Ras mutations are rare in solitary cold and toxic thyroid nodules. Clin Endocrinol. 2001;55(2):241–8.CrossRefGoogle Scholar
  110. Krohn K, Stricker I, Emmrich P, Paschke R. Cold thyroid nodules show a marked increase in proliferation markers. Thyroid. 2003;13(6):569–75.PubMedCrossRefPubMedCentralGoogle Scholar
  111. Krohn K, Fuhrer D, Bayer Y, et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev. 2005;26(4):504–24.PubMedCrossRefPubMedCentralGoogle Scholar
  112. Krohn K, Maier J, Paschke R. Mechanisms of disease: hydrogen peroxide, DNA damage and mutagenesis in the development of thyroid tumors. Nat Clin Pract Endocrinol Metab. 2007;3(10):713–20.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Kuma K, Matsuzuka F, Kobayashi A, et al. Outcome of long standing solitary thyroid nodules. World J Surg. 1992;16(4):583–7.PubMedCrossRefPubMedCentralGoogle Scholar
  114. L’assurance maladie – Caisse Nationale. Pertinence des soins: une analyse de la pratique des thyroidectomies chez l’adulte. http://www.ameli.fr/fileadmin/user_upload/documents/23102013_DP_thyroidectomies.pdf. 2013. Ref Type: Online Source.
  115. Labourier E, Shifrin A, Busseniers AE, et al. Molecular testing for miRNA, mRNA and DNA on fine needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. J Clin Endocrinol Metab. 2015;100(7):2743–50.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Lang W, Georgii A, Stauch G, Kienzle E. The differentiation of atypical adenomas and encapsulated follicular carcinomas in the thyroid gland. Virchows Arch A Pathol Anat Histol. 1980;385(2):125–41.PubMedCrossRefPubMedCentralGoogle Scholar
  117. Laulund AS, Nybo M, Brix TH, Abrahamsen B, Jorgensen HL, Hegedus L. Duration of thyroid dysfunction correlates with all-cause mortality. the OPENTHYRO Register Cohort. PLoS ONE. 2014;9(10):e110437.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Lazar V, Bidart JM, Caillou B, et al. Expression of the Na+/I− symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab. 1999;84(9):3228–34.PubMedPubMedCentralGoogle Scholar
  119. Lee SR, Jung CK, Kim TE, et al. Molecular genotyping of follicular variant of papillary thyroid carcinoma correlates with diagnostic category of fine-needle aspiration cytology: values of RAS mutation testing. Thyroid. 2013;23(11):1416–22.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Lewis CM, Chang KP, Pitman M, Faquin WC, Randolph GW. Thyroid fine-needle aspiration biopsy: variability in reporting. Thyroid. 2009;19(7):717–23.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011;96(11):E1719–26.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Lim DJ, Kim JY, Baek KH, et al. Natural course of cytologically benign thyroid nodules: observation of ultrasonographic changes. Endocrinol Metab (Seoul). 2013;28(2):110–8.CrossRefGoogle Scholar
  123. Liu RT, Hou CY, You HL, et al. Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 2004;14(8):616–21.PubMedCrossRefPubMedCentralGoogle Scholar
  124. Lodewijk L, Prins AM, Kist JW, et al. The value of miRNA in diagnosing thyroid cancer: a systematic review. Cancer Biomark. 2012;11(6):229–38.PubMedCrossRefPubMedCentralGoogle Scholar
  125. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Marinelli LD, Quimby EH, Hine GJ. Dosage determination with radioactive isotopes; practical considerations in therapy and protection. Am J Roentgenol Radium Ther. 1948;59(2):260–81.PubMedPubMedCentralGoogle Scholar
  127. Marques AR, Espadinha C, Catarino AL, et al. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab. 2002;87(8):3947–52.PubMedPubMedCentralGoogle Scholar
  128. Marti JL, Avadhani V, Donatelli LA, et al. Wide inter-institutional variation in performance of a molecular classifier for indeterminate thyroid nodules. Ann Surg Oncol. 2015;22(12):3996–4001.PubMedPubMedCentralCrossRefGoogle Scholar
  129. McIver B. Evaluation of the thyroid nodule. Oral Oncol. 2013;49(7):645–53.PubMedCrossRefPubMedCentralGoogle Scholar
  130. McIver B, Castro MR, Morris JC, et al. An independent study of a gene expression classifier (Afirma) in the evaluation of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2014;99(11):4069–77.PubMedCrossRefPubMedCentralGoogle Scholar
  131. Medici M, Kwong N, Angell TE, et al. The variable phenotype and low-risk nature of RAS-positive thyroid nodules. BMC Med. 2015;13:184.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Mian C, Lacroix L, Alzieu L, et al. Sodium iodide symporter and pendrin expression in human thyroid tissues. Thyroid. 2001;11(9):825–30.PubMedCrossRefPubMedCentralGoogle Scholar
  133. Moses W, Weng J, Sansano I, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg. 2010;34(11):2589–94.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Najafzadeh M, Marra CA, Lynd LD, Wiseman SM. Cost-effectiveness of using a molecular diagnostic test to improve preoperative diagnosis of thyroid cancer. Value Health. 2012;15(8):1005–13.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Nikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecular testing for mutations in improving the fine needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009;94(6):2092–8.PubMedCrossRefPubMedCentralGoogle Scholar
  136. Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96(11):3390–7.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Nikiforov YE, Carty SE, Chiosea SI, et al. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;120(23):3627–34.PubMedCrossRefPubMedCentralGoogle Scholar
  138. Nikiforov YE, Carty SE, Chiosea SI, et al. Impact of the multi-gene ThyroSeq next-generation sequencing assay on cancer diagnosis in thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology. Thyroid. 2015;25(11):1217–23.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Nikiforov YE, Seethala RR, Tallini G et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016.Google Scholar
  140. Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol. 2002;26(8):1016–23.PubMedCrossRefPubMedCentralGoogle Scholar
  141. Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE. Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab. 2013;98(11):E1852–60.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Nishino M. Molecular cytopathology for thyroid nodules: A review of methodology and test performance. Cancer Cytopathol. 2016;124(1):14–27.PubMedCrossRefPubMedCentralGoogle Scholar
  143. Nou E, Kwong N, Alexander LK, Cibas ES, Marqusee E, Alexander EK. Determination of the optimal time interval for repeat evaluation after a benign thyroid nodule aspiration. J Clin Endocrinol Metab. 2014;99(2):510–6.PubMedCrossRefPubMedCentralGoogle Scholar
  144. Nygaard B, Hegedus L, Nielsen KG, Ulriksen P, Hansen JM. Long-term effect of radioactive iodine on thyroid function and size in patients with solitary autonomously functioning toxic thyroid nodules. Clin Endocrinol. 1999;50(2):197–202.CrossRefGoogle Scholar
  145. Oertel YC, Miyahara-Felipe L, Mendoza MG, Yu K. Value of repeated fine needle aspirations of the thyroid: an analysis of over ten thousand FNAs. Thyroid. 2007;17(11):1061–6.PubMedCrossRefPubMedCentralGoogle Scholar
  146. Ohori NP, Nikiforova MN, Schoedel KE, et al. Contribution of molecular testing to thyroid fine-needle aspiration cytology of “follicular lesion of undetermined significance/atypia of undetermined significance”. Cancer Cytopathol. 2010;118(1):17–23.PubMedCrossRefPubMedCentralGoogle Scholar
  147. Okumura Y, Takeda Y, Sato S, et al. Comparison of differential diagnostic capabilities of 201Tl scintigraphy and fine-needle aspiration of thyroid nodules. J Nucl Med. 1999;40(12):1971–7.PubMedPubMedCentralGoogle Scholar
  148. Pagan M, Kloos RT, Lin CF, et al. The diagnostic application of RNA sequencing in patients with thyroid cancer: an analysis of 851 variants and 133 fusions in 524 genes. BMC Bioinformatics. 2016;17(Suppl 1):6.PubMedPubMedCentralCrossRefGoogle Scholar
  149. Panzer C, Beazley R, Braverman L. Rapid preoperative preparation for severe hyperthyroid Graves’ disease. J Clin Endocrinol Metab. 2004;89(5):2142–4.PubMedCrossRefPubMedCentralGoogle Scholar
  150. Papini E, Pacella CM, Misischi I, et al. The advent of ultrasound-guided ablation techniques in nodular thyroid disease: towards a patient-tailored approach. Best Pract Res Clin Endocrinol Metab. 2014a;28(4):601–18.PubMedCrossRefPubMedCentralGoogle Scholar
  151. Papini E, Pacella CM, Hegedus L. Diagnosis of endocrine disease: thyroid ultrasound (US) and US-assisted procedures: from the shadows into an array of applications. Eur J Endocrinol. 2014b;170(4):R133–46.PubMedCrossRefPubMedCentralGoogle Scholar
  152. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358(9285):861–5.PubMedCrossRefPubMedCentralGoogle Scholar
  153. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 1993;365(6447):649–51.PubMedCrossRefPubMedCentralGoogle Scholar
  154. Pisarev MA, Krawiec L, Juvenal GJ, et al. Studies on the goiter inhibiting action of iodolactones. Eur J Pharmacol. 1994;258(1–2):33–7.PubMedCrossRefPubMedCentralGoogle Scholar
  155. Puxeddu E, Moretti S, Elisei R, et al. BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab. 2004;89(5):2414–20.PubMedCrossRefPubMedCentralGoogle Scholar
  156. Rago T, Santini F, Scutari M, Pinchera A, Vitti P. Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules. J Clin Endocrinol Metab. 2007;92(8):2917–22.PubMedPubMedCentralCrossRefGoogle Scholar
  157. Reiners C, Schneider P. Radioiodine therapy of thyroid autonomy. Eur J Nucl Med Mol Imaging. 2002;29(Suppl 2):S471–8.PubMedCrossRefPubMedCentralGoogle Scholar
  158. Reschini E, Ferrari C, Castellani M, et al. The trapping-only nodules of the thyroid gland: prevalence study. Thyroid. 2006;16(8):757–62.PubMedCrossRefPubMedCentralGoogle Scholar
  159. Rippe V, Drieschner N, Meiboom M, et al. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene. 2003;22(38):6111–4.PubMedCrossRefPubMedCentralGoogle Scholar
  160. Rivera M, Ricarte-Filho J, Knauf J, et al. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. 2010;23(9):1191–200.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Rochefort P, Caillou B, Michiels FM, et al. Thyroid pathologies in transgenic mice expressing a human activated Ras gene driven by a thyroglobulin promoter. Oncogene. 1996;12(1):111–8.PubMedPubMedCentralGoogle Scholar
  162. Roger PP, Servais P, Dumont JE. Stimulation by thyrotropin and cyclic AMP of the proliferation of quiescent canine thyroid cells cultured in a defined medium containing insulin. FEBS Lett. 1983;157(2):323–9.PubMedCrossRefPubMedCentralGoogle Scholar
  163. Rossing M. Classification of follicular cell-derived thyroid cancer by global RNA profiling. J Mol Endocrinol. 2013;50(2):R39–51.PubMedCrossRefPubMedCentralGoogle Scholar
  164. Russ G, Royer B, Bigorgne C, Rouxel A, Bienvenu-Perrard M, Leenhardt L. Prospective evaluation of thyroid imaging reporting and data system on 4550 nodules with and without elastography. Eur J Endocrinol. 2013;168(5):649–55.CrossRefPubMedGoogle Scholar
  165. Ryo UY, Vaidya PV, Schneider AB, Bekerman C, Pinsky SM. Thyroid imaging agents: a comparison of I-123 and Tc-99m pertechnetate. Radiology. 1983;148(3):819–22.PubMedCrossRefGoogle Scholar
  166. Saavedra HI, Knauf JA, Shirokawa JM, et al. The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene. 2000;19(34):3948–54.PubMedCrossRefPubMedCentralGoogle Scholar
  167. Sandrock D, Olbricht T, Emrich D, Benker G, Reinwein D. Long-term follow-up in patients with autonomous thyroid adenoma. Acta Endocrinol. 1993;128(1):51–5.PubMedPubMedCentralCrossRefGoogle Scholar
  168. Sapio MR, Guerra A, Marotta V, et al. High growth rate of benign thyroid nodules bearing RET/PTC rearrangements. J Clin Endocrinol Metab. 2011;96(6):E916–9.PubMedCrossRefPubMedCentralGoogle Scholar
  169. Schroder S, Marthaler B. Autonomy and malignancy of thyroid glad tumors. A critical analysis of the literature on the existence of hyperfunctioning follicular and papillary thyroid gland carcinomas. Pathologe. 1996;17(5):349–57.PubMedCrossRefPubMedCentralGoogle Scholar
  170. Schulten HJ, Salama S, Al-Ahmadi A, et al. Comprehensive survey of HRAS, KRAS, and NRAS mutations in proliferative thyroid lesions from an ethnically diverse population. Anticancer Res. 2013;33(11):4779–84.PubMedPubMedCentralGoogle Scholar
  171. Sebastianes FM, Cerci JJ, Zanoni PH, et al. Role of 18F-fluorodeoxyglucose positron emission tomography in preoperative assessment of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2007;92(11):4485–8.PubMedCrossRefPubMedCentralGoogle Scholar
  172. Smith TJ, Hegedus L. Graves’ disease. N Engl J Med. 2016;375(16):1552–65.PubMedPubMedCentralCrossRefGoogle Scholar
  173. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22(29):4578–80.PubMedCrossRefPubMedCentralGoogle Scholar
  174. Soelberg KK, Bonnema SJ, Brix TH, Hegedus L. Risk of malignancy in thyroid incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography: a systematic review. Thyroid. 2012;22(9):918–25.PubMedCrossRefPubMedCentralGoogle Scholar
  175. Stokowy T, Wojtas B, Fujarewicz K, Jarzab B, Eszlinger M, Paschke R. miRNAs with the potential to distinguish follicular thyroid carcinomas from benign follicular thyroid tumors – results of a meta-analysis. Horm Metab Res. 2013;46(3):171–80.Google Scholar
  176. Stokowy T, Wojtas B, Krajewska J, et al. A two miRNA classifier differentiates follicular thyroid carcinomas from follicular thyroid adenomas. Mol Cell Endocrinol. 2015;399:43–9.PubMedCrossRefPubMedCentralGoogle Scholar
  177. Stokowy T, Wojtas B, Jarzab B, et al. Two-miRNA-classifiers differentiate mutation-negative follicular thyroid carcinomas and follicular thyroid adenomas in Fine Needle Aspirations with high specificity. Endocrine. 2016;54(2):440–7.PubMedCrossRefPubMedCentralGoogle Scholar
  178. Strickland KC, Howitt BE, Marqusee E, et al. The impact of noninvasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25(9):987–92.PubMedCrossRefPubMedCentralGoogle Scholar
  179. Studer H, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev. 1989;10(2):125–35.PubMedCrossRefPubMedCentralGoogle Scholar
  180. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228–38.PubMedCrossRefPubMedCentralGoogle Scholar
  181. Taton M, Lamy F, Roger PP, Dumont JE. General inhibition by transforming growth factor beta 1 of thyrotropin and cAMP responses in human thyroid cells in primary culture. Mol Cell Endocrinol. 1993;95(1–2):13–21.PubMedCrossRefPubMedCentralGoogle Scholar
  182. Thomusch O, Machens A, Sekulla C, et al. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: prospective multicenter study in Germany. World J Surg. 2000;24(11):1335–41.PubMedCrossRefPubMedCentralGoogle Scholar
  183. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med. 2001;345(7):512–6.PubMedCrossRefPubMedCentralGoogle Scholar
  184. Tonacchera M, Viacava P, Agretti P, et al. Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein. J Clin Endocrinol Metab. 2002;87(1):352–7.PubMedCrossRefPubMedCentralGoogle Scholar
  185. Trivalle C, Doucet J, Chassagne P, et al. Differences in the signs and symptoms of hyperthyroidism in older and younger patients. J Am Geriatr Soc. 1996;44(1):50–3.PubMedCrossRefPubMedCentralGoogle Scholar
  186. Trulzsch B, Krohn K, Wonerow P, Paschke R. DGGE is more sensitive for the detection of somatic point mutations than direct sequencing. Biotechniques. 1999;27(2):266–8.PubMedPubMedCentralCrossRefGoogle Scholar
  187. Trulzsch B, Krohn K, Wonerow P, et al. Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis. J Mol Med. 2001;78(12):684–91.PubMedCrossRefPubMedCentralGoogle Scholar
  188. Tuttle RM, Ball DW, Byrd D, et al. Thyroid carcinoma. J Natl Compr Cancer Netw. 2010;8(11):1228–74.CrossRefGoogle Scholar
  189. Tuttle RM, Haddad RI, Ball DW, et al. Thyroid carcinoma, version 2.2014. J Natl Compr Cancer Netw. 2014;12(12):1671–80.CrossRefGoogle Scholar
  190. van den Bruel A, Francart J, Dubois C, et al. Regional variation in thyroid cancer incidence in Belgium is associated with variation in thyroid imaging and thyroid disease management. J Clin Endocrinol Metab. 2013;98(10):4063–71.PubMedCrossRefPubMedCentralGoogle Scholar
  191. Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab. 1995;80(9):2577–85.PubMedPubMedCentralGoogle Scholar
  192. Vanderlaan PA, Krane JF, Cibas ES. The frequency of ‘atypia of undetermined significance’ interpretations for thyroid fine-needle aspirations is negatively correlated with histologically proven malignant outcomes. Acta Cytol. 2011;55(6):512–7.PubMedCrossRefPubMedCentralGoogle Scholar
  193. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88(6):2745–52.PubMedCrossRefPubMedCentralGoogle Scholar
  194. Vassart G. Activating mutations of the TSH receptor. Thyroid. 2004;14(1):86–7.PubMedCrossRefPubMedCentralGoogle Scholar
  195. Vidal-Trecan GM, Stahl JE, Durand-Zaleski I. Managing toxic thyroid adenoma: a cost-effectiveness analysis. Eur J Endocrinol. 2002;146(3):283–94.PubMedCrossRefPubMedCentralGoogle Scholar
  196. Walsh PS, Wilde JI, Tom EY, et al. Analytical performance verification of a molecular diagnostic for cytology-indeterminate thyroid nodules. J Clin Endocrinol Metab. 2012;97(12):E2297–306.PubMedCrossRefPubMedCentralGoogle Scholar
  197. Walter MA, Briel M, Christ-Crain M, et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ. 2007;334(7592):514.PubMedPubMedCentralCrossRefGoogle Scholar
  198. Wang CC, Friedman L, Kennedy GC, et al. A large multicenter correlation study of thyroid nodule cytopathology and histopathology. Thyroid. 2011;21(3):243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  199. Ward LS, Brenta G, Medvedovic M, Fagin JA. Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab. 1998;83(2):525–30.PubMedPubMedCentralGoogle Scholar
  200. Watt T, Bjorner JB, Groenvold M, et al. Development of a short version of the thyroid-related patient-reported outcome ThyPRO. Thyroid. 2015;25(10):1069–79.PubMedCrossRefPubMedCentralGoogle Scholar
  201. Weetman AP. Radioiodine treatment for benign thyroid diseases. Clin Endocrinol. 2007; 66(6):757–64.CrossRefGoogle Scholar
  202. Wienhold R, Scholz M, Adler JR, Nster G, Paschke R. The management of thyroid nodules: a retrospective analysis of health insurance data. Dtsch Arztebl Int. 2013;110(49):827–34.PubMedPubMedCentralGoogle Scholar
  203. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013; 13(3):184–99.PubMedPubMedCentralCrossRefGoogle Scholar
  204. Xing M, Vasko V, Tallini G, et al. BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab. 2004;89(3):1365–8.PubMedCrossRefPubMedCentralGoogle Scholar
  205. Yip L. Molecular markers for thyroid cancer diagnosis, prognosis, and targeted therapy. J Surg Oncol. 2015;111(1):43–50.PubMedCrossRefPubMedCentralGoogle Scholar
  206. Yoo SK, Lee S, Kim SJ, et al. Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers. PLoS Genet. 2016;12(8):e1006239.PubMedPubMedCentralCrossRefGoogle Scholar
  207. Yoon JH, Kwon HJ, Lee HS, Kim EK, Moon HJ, Kwak JY. RAS mutations in AUS/FLUS cytology: does it have an additional role in BRAFV600E mutation-negative nodules? Medicine (Baltimore). 2015;94(27):e1084.CrossRefGoogle Scholar
  208. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 2003;120(1):71–7.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Markus Eszlinger
    • 1
  • Laszlo Hegedüs
    • 2
  • Ralf Paschke
    • 3
  1. 1.Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
  2. 2.Department of Endocrinology and MetabolismOdense University HospitalOdenseDenmark
  3. 3.Section of Endocrinology and Metabolism, Departments of Medicine, Oncology, Biochemistry and Molecular Biology and Arnie Charbonneau Cancer Institute, Cumming School of MedicineUniversity of CalgaryCalgaryCanada

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