Molecular Cytology Application on Thyroid

  • Esther Diana RossiEmail author
  • Massimo Bongiovanni


The detection of thyroid nodules (TN) represents a common finding in population. Their evaluation and diagnosis are mostly achieved with fine-needle aspiration cytology (FNAC) which is increasing due to the reliance upon sonographic and detection of millimeter lesions. The cytological evaluation of both palpable and not-palpable thyroid lesions represents a challenge for pathologists and cytopathologists. The correct cytological discrimination between benign and malignant lesions is the first invaluable point for the adequate clinical and/or surgical management of thyroid lesions. Even though the majority of TNs are correctly diagnosed, a total 25–30% of them are classified as follicular neoplasms (FN) comprising lesions with varying risk of malignancy and different management.

Due to the issue in the morphological interpretations and inter-observer reproducibility especially among the FNs, the best results have been obtained with the support of ancillary techniques (e.g., immunocytochemistry-ICC and molecular analysis) which are reshaping the practice of FNAC and the diagnosis of thyroid lesions. Their application, due to the high specificity, contributes to obtain the best results as a complement analysis allowing more specific and tailored therapeutic strategies. Even though many markers are in development and have been studied, two principal tests are currently used to improve the malignant risk assessment of thyroid lesions. These “rule in “and “rule out” tests are able to confirm or exclude, respectively, the presence of cancer within a thyroid nodule.

We overviewed the role of molecular testing in different cytological methods (i.e., conventional cytology, liquid based cytology, cell-blocks).


Thyroid gland Thyroid lesions Thyroid carcinoma Papillary thyroid carcinoma Medullary carcinoma Poorly differentiated thyroid carcinoma Immunocytochemistry Molecular analysis miRNA Gene expression classifier 


  1. 1.
    Lee V, Ng SB, Salto-Tellez M. New techniques. In: Dabbs I, editor. Diagnostic immunohistochemistry. Theranostic and genomic application. 3rd ed. saunder, elsevier, philadelphia.CrossRefGoogle Scholar
  2. 2.
    Salto-Telle M, Koay S. Molecular dignostic cytopathology: definitions, scope, and clinical utility. Cytopathology. 2004;15:252–5.CrossRefGoogle Scholar
  3. 3.
    Ng SB, Lee V, Salto-Tellez M. The relevance of molecular diagnostics in the practice of surgical pathology. Expert Opin Med Diagn. 2008;2:1401–14.CrossRefGoogle Scholar
  4. 4.
    Srinivassan M, Sedmak D, Jewell S. Effect of fixatives and tissue processing on the content and integraty of nucleic acid. Am J Pathol. 2002;161:1961–71.CrossRefGoogle Scholar
  5. 5.
    Sapio MR, Posca D, Raggioli A, et al. Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings. Clin Endocrin. 2007;66:678–83.CrossRefGoogle Scholar
  6. 6.
    Rossi ED, Schmitt FC. Pre-analytic steps for molecular testing on thyroid fine-needle aspirations: the goal of good results. Cytojournal. 2013;28:10–24.Google Scholar
  7. 7.
    Da Cunha SG. Standardizing preanalytical variables for molecular cytopathology. Cancer Cytopathol. 2013;121:341–3.CrossRefGoogle Scholar
  8. 8.
    Cramer H. Fine-needle aspiration cytology of the thyroid: an appraisal. Cancer. 2000;90:325–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Gharib H, Papini E, Paschke R. Thyroid nodules: a review of current guidelines, practices and prospects. Eur J Endocrinol. 2008;159:493–505.PubMedCrossRefGoogle Scholar
  10. 10.
    The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of the Papanicolaou society of cytopathology for the examination of fine needle aspirationspecimens from thyroid nodules. Mod Pathol. 1996;9:710–5.Google Scholar
  11. 11.
    Cooper DS, Doherty GM, Haugen BR, et al. American Thyroid Association (ATA) guidelines taskforce on thyroid nodules and differentiated thyroid cancer. Revised management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214.PubMedCrossRefGoogle Scholar
  12. 12.
    Gharib H, Papini E, Valcavi R, et al. Aace/ame Task Force on Thyroid Nodules:. American Association of clinical endocrinologists and associazione medici endocrinology and European thyroid association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract. 2006;12(63-102):1–43.Google Scholar
  13. 13.
    Lobo C, McQueen A, Beale T, et al. The UK royal college of pathologists thyroid fine-needle aspiration diagnostic classification is a robust tool for the clinical management of abnormal thyroid nodules. Acta Citologica. 2011;55:499–506.CrossRefGoogle Scholar
  14. 14.
    Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Fine-needle aspiration state-of-science conference. Diagn Cytopathol. 2008;36:425–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Cibas ED, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathology. 2001;32:658–65.Google Scholar
  16. 16.
    Bongiovanni M, Spitale A, Faquin WC, et al. The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytologica. 2012;56:333–9.PubMedCrossRefGoogle Scholar
  17. 17.
    British Thyroid Association, Royal College of Physicians. Guidelines for the management of thyroid cancer. In: Perros P, editor. Report of the Thyroid Cancer Guidelines Update Group. 2nd ed. London: Royal College of Physicians; 2007.Google Scholar
  18. 18.
    Fadda G, Basolo F, Bondi A, et al. SIAPEC-IAP Italian Consensus Working Group. Cytological classification of thyroid nodules. Proposal of the SIAPEC-IAP Italian consensus working group. Pathologica. 2010;102:405–8.PubMedGoogle Scholar
  19. 19.
    Cochand Priollet B, Schmitt FC, Totsch M, et al. The Bethesda terminology for reporting thyroid cytopathology: from theory to practice in Europe. Acta Cytol. 2011;55:507–17.PubMedCrossRefGoogle Scholar
  20. 20.
    Nardi F, Basolo F, Crescenzi A, et al. Italian consensus for the classification and reporting of thyroid cytology. J Endocrinol Invest. 2014;37:593–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Royal College of pathologists of Australasia. Thyroid cytologystructured reporting protocol. 9624e686404/Protocol-thyroid-FNA-cytology.aspx. Accessed October 9, 2015Google Scholar
  22. 22.
    Raab SS, Vrbin CM, Grzybicki DM, et al. Errors in thyroid gland fine-needle aspiration. Am J Clin Pathol. 2006;125:873–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Broome JT, Solorzano CC. The impact of atypia/follicular lesion of undetermined significance on the rate of malignancy in thyroid fine-needle aspiration: evaluation of the Bethesda System for Reporting Thyroid Cytopathology. Surgery. 2011;150:1234–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Ravetto C, Colombo L, Dottorini ME. Usefulness of fine- needle aspiration in the diagnosis of thyroid carcinomas. A retrospective study in 37,895 patients. Cancer Cytopathol. 2000;90:357–63.CrossRefGoogle Scholar
  25. 25.
    Poller DN, Ibrahim AK, Cummings MH, et al. Fine-needle aspiration of the thyroid. Importance of an indeterminate diagnostic category. Cancer Cytopathol. 2000;90:239–44.CrossRefGoogle Scholar
  26. 26.
    Krane JF, Vanderlaan PA, Faquin WC, et al. The atypia of undetermined significance/follicular lesion of undetermined significance:malignant ratio. Cancer Cytopathol. 2012;120:111–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Ho AS, Sarti EE, Jain KS, et al. Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS). Thyroid. 2014;24:832–9.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Song JY, Chu YC, Kim L, et al. Reclassifying formerly indeterminate thyroid FNAs using the Bethesda system reduces the number of inconclusive cases. Acta Cytol. 2012;56:122–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Shi Y, Ding X, Klein M, et al. Thyroid fine-needle aspiration with atypia of undetermined significance: a necessary or optional category? Cancer. 2009;117:298–304.PubMedGoogle Scholar
  30. 30.
    Damiani D, Suciu V, Vielh P. Cytopathology of follicular cell nodules. Endocr Pathol. 2015;26:286–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Nagarkatti SS, Faquin WC, Lubitz CC, et al. Management of thyroid nodules with atypical cytology on fine-needle aspiration biopsy. Ann Surg Oncol. 2013;20:60–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Olson MT, Clark DP, Erozan YS, et al. Spectrum of risk of malignancy in subcategories of ‘atypia of undetermined significance’. Acta Cytol. 2011;55:518–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Horne MJ, Chhieng DC, Theoharis C, et al. Thyroid follicular lesion of undetermined significance: evaluation of the risk of malignancy using the two-tier sub-classification. Diagn Cytopathol. 2012;40:410–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Hyeon J, Ahn S, Shin JH, et al. The prediction of malignant risk in the category “atypia of undetermined significance/follicular lesion of undetermined significance” of the Bethesda System for Reporting Thyroid Cytopathology using subcategorization and BRAF mutation results. Cancer Cytopathol. 2014;122:368–76.PubMedCrossRefGoogle Scholar
  35. 35.
    Dincer N, Balci S, Yazgan A, et al. Follow-up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology. Cytopathology. 2013;24:385–90.PubMedCrossRefGoogle Scholar
  36. 36.
    Gocun PU, Karakus E, Bulutay P, et al. What is the malignancy risk for atypia of undetermined significance?: Three Years’ Experience at a University Hospital in Turkey. Cancer Cytopathol. 2014;122:604–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Wu HH, Inman A, Cramer HM. Subclassification of “Atypia of Undetermined Significance” in thyroid fine-needle aspirates. Diagn Cytopathol. 2014;42:23–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Borget I, Vielh P, Leboullex S, et al. Assessment of the cost of fine-needle aspiration cytology as a diagnostic tool in patients with thyroid nodules. Am J Clin Pathol. 2008;129:763–71.PubMedCrossRefGoogle Scholar
  39. 39.
    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;2(8):1023–9.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Maletta F, Massa F, Torregrossa L, et al. Cytological features of “invasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum Pathol. 2016;54:134–42.PubMedCrossRefGoogle Scholar
  41. 41.
    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;124:181–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Lastra RR, LiVolsi VA, Baloch ZW. Aggressive variants of follicular cell-derived thyroid carcinomas: a cytopathologist’s perspective. Cancer Cytopathol. 2014;122:484–503.PubMedCrossRefGoogle Scholar
  43. 43.
    Strickland KC, Howitt BE, Marquese 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;25:987–92.PubMedCrossRefGoogle Scholar
  44. 44.
    Correia-Rodrigues HG, Nogueira De Pontes AA, et al. Use of molecular markers in samples obtained from preoperative aspiration of thyroid. Endocr J. 2012;59:417–24.CrossRefGoogle Scholar
  45. 45.
    Paunovic I, Isic T, Havelka M, et al. Combined immunohistochemistry fro thyroid peroxidase, Galectin-3 and HBME-1 in different diagnosis of thyroid tumors. APMIS. 2012;120:368–79.PubMedCrossRefGoogle Scholar
  46. 46.
    Chiu CG, Strugnell SS, Griffith OL, et al. Diagnostic utility of galectin-3 in thyroid cancer. Am J Pathol. 2010;176:2067–81.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Bartolazzi A, Orlandi F, Saggiorato E, et al. Italian Thyroid Cancer Study Group (ITCSG).Galectin-3 expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study. Lancet Oncol. 2008;9:543–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Prasad ML, Pellegata NS, Huang Y, et al. Galectin-3, fibronectin-1, CITED-1, HBME-1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol. 2005;18:48–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Rossi ED. Who was responsible for reaching the Americas-Columbus or his ships?: Focusing on the side of liquid-based cytology: the importance and role of the cytopathologist as opposed to the cytological method used. Cancer Cytopathol. 2014;122:337–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Herrmann ME, LiVolsi VA, Pasha TL, et al. Immunohistochemical expression of Galectin-3 in benign and malignant thyroid lesions. Arch Pathol Lab Med. 2002;126:710–3.PubMedGoogle Scholar
  51. 51.
    Schmitt FC, Barroca H. Role of ancillary studies in fine needle aspiration from selected tumors. Cancer Cytopathol. 2012;120:145–60.PubMedCrossRefGoogle Scholar
  52. 52.
    Schmitt FC, Longatto-Filho A, Valent A, et al. Molecular techniques in cytopathology practice. J Clin Pathol. 2008;61:258–67.CrossRefPubMedGoogle Scholar
  53. 53.
    Longatto-Filho A, Goncalves AE, Martinho O, et al. Liquid based cytology in DNA-based molecular research. Anal Quant Cytol Histol. 2009;31:395–400.Google Scholar
  54. 54.
    Nikiforova MN, Nikiforov Y. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009;19:1351–61.PubMedCrossRefGoogle Scholar
  55. 55.
    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;94:2092–8.PubMedCrossRefGoogle Scholar
  56. 56.
    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;118:17–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Fadda G, Rossi ED. Liquid based cytology in fine needle aspiration biopsies of the thyroid gland. Acta Cytol. 2011;55:389–400.PubMedCrossRefGoogle Scholar
  58. 58.
    Rossi ED, Martini M, Capodimonti S, et al. BRAF (v600e) mutation analysis on LBC-processed aspiration biopsies predicts bilaterality and nodal involvement in papillary thyroid microcarcinoma. Cancer Cytopathol. 2013;121:291–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Rossi ED, Martini M, Capodimonti S, et al. Diagnostic and prognostic value of immunocytochemistry and BRAF mutation analysis on liquid based biopsies of thyroid neoplasms suspicious for carcinoma. Eur J Endocrin. 2013;168:853–9.CrossRefGoogle Scholar
  60. 60.
    Chang H, Lee H, Yoon SO, et al. BRAF (V600E) mutation analysis of liquid-based preparation-processed fine needle aspiration sample improves the diagnostic rate of papillary thyroid carcinoma. Human Pathol. 2012;43:89–95.CrossRefGoogle Scholar
  61. 61.
    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;34:2589–94.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Xing M. Braf mutationin papillary thyroid cancer:pathogenic role,molecular bases,and clinical implications. Endocr Rev. 2007;28:742–62.PubMedCrossRefGoogle Scholar
  63. 63.
    Puxeddu E, Durante C, Avenia N, et al. Clinical implications of BRAF mutation in thyroid carcinoma. Trends Endocrinol Metab. 2008;19:138–45.PubMedCrossRefGoogle Scholar
  64. 64.
    Colanta A, Lin O, Tafe L, et al. BRAF mutation analysis of fine-needle aspiration biopsies of papillary thyroid carcinoma: impact on diagnosis and prognosis. Acta Cytolog. 2011;55:563–9.CrossRefGoogle Scholar
  65. 65.
    Moura MM, Cavaco BM, Leite V. RAS-protooncogene in medullary thyroid carcinoma. Endocr Relat Cancer. 2015;22:R235–52.PubMedCrossRefGoogle Scholar
  66. 66.
    Tamburrino A, Molinolo AA, Salerno P. Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases. Clin Cancer Res. 2012;18:3532–40.PubMedCrossRefGoogle Scholar
  67. 67.
    Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2:851–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363:458–60.PubMedCrossRefGoogle Scholar
  69. 69.
    Carlson KM, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994;91:1579–83.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367:375–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Eng C, Smith DP, Mulligan LM, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3:237–41.PubMedCrossRefGoogle Scholar
  72. 72.
    Marsh DJ, Learoyd DL, Andrew SD, et al. Somatic mutations in the RET proto-oncogene in sporadic 97 medullary thyroid carcinoma. Clin Endocrinol. 1996;44:249–57.CrossRefGoogle Scholar
  73. 73.
    Moura MM, Cavaco BM, Pinto AE, et al. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 2011;6:E863–8.CrossRefGoogle Scholar
  74. 74.
    Boichard A, Croux L, Al Ghuzlan A, et al. Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. J Clin Endocrinol Metab. 2012;97:E2031–5.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Ciampi R, Mian C, Fugazzola L, et al. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid. 2013;23:50–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98:E364–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Schilling T, Burck J, Sinn HP, et al. Prognostic value of codon 918 (ATG-->ACG) RET protooncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001;9(5):62–6.CrossRefGoogle Scholar
  78. 78.
    Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93:682–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Volante M, Rapa I, Gandhi M, et al. Ras mutation as the predominant nuclear alteration in poorly differentiated thyroid carcinoma and bear prognostic impact. J Clin Endocrinol Metab. 2009;94:4735–41.PubMedCrossRefGoogle Scholar
  80. 80.
    Volante M, Rapa I, Papotti M. Poorly differentiated thyroid carcinoma: diagnostic features and controversial issues. Endocr Pathol. 2008;19:150–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Rocha AS, Soares P, Fonseca E, et al. E-cadherin loss rather β-alteration is a common feature of poorly differentiated thyroid carcinomas. Histopathology. 2003;42:580–7.PubMedCrossRefGoogle Scholar
  82. 82.
    De Falco V, Guarino V, Avilla E, et al. Biological role and potential therapeutic targeting of the chemokine receptor CXCR4 in undifferentiated thyroid cancer. Cancer Res. 2007;67:1821–9.Google Scholar
  83. 83.
    Nikiforova MN, Kimura ET, Gandhi M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinoma and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2008;88:5399–404.CrossRefGoogle Scholar
  84. 84.
    Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.CrossRefGoogle Scholar
  85. 85.
    Ferris RL, Baloch ZW, Bernet V, et al. The American Thyroid Association Surgical Affairs Committee. American Thyroid Association Statement on Surgical Application of Molecular Profiling for Thyroid Nodules: Current Impact on Perioperative Decision Making. Thyroid. 2015;25:760–8.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Rossi ED, Bizzaro T, Longatto-Filho A, et al. The diagnostic and prognostic role of liquid-based cytology: are we ready to monitor therapy and resistance? Expert Rev Anticancer Ther. 2015;15:911–21.PubMedCrossRefGoogle Scholar
  87. 87.
    Soares P, Trovisco V, Rocha AS, et al. M.BRAF mutations and RET/PTC rearrangements are alternative events in the ethiopathogenesis of PTC. Oncogene. 2003;22:4578–80.PubMedCrossRefGoogle Scholar
  88. 88.
    Park SY, Park YJ, Lee YJ, et al. Analysis of differential BRAF (V600E) mutational status in multifocal papillary thyroid carcinoma. Evidence of independent clonal origin in distinct tumor foci. Cancer. 2006;107:1831–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Soares P, Trovisco V, Rocha AS, et al. Braf mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas. Virchows Arch. 2004;444:572–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Elisei R, Ugolini C, Viola D, et al. BRAF mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab. 2008;93:3943–50.PubMedCrossRefGoogle Scholar
  91. 91.
    La R, Chiosea SI, Seethala RR, et al. Thyroid nodules with KRAS mutations are different from nodules with NRAS and HRAS mutations with regard to cytopathologic and histopathologic outcome characteristics. Cancer Cytopathol. 2014;122:873–82.CrossRefGoogle Scholar
  92. 92.
    Nikiforov YE, Carry SE, Chiosea SI, et al. Impact of the multigene ThyroSeq next generation sequencing assay on cancer diagnosis in thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology. Thyroid. 2015;120:3627–34.Google Scholar
  93. 93.
    Nikiforova MN, Wald AI, Roy S, et al. Targeted next-generation sequencing panel (Thyro Seq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab. 2013;98:E1852–60.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Nikiforov YE, Carty SE, Chiosea SI, et al. Highly accurate diagnosis of cancer in thyroid nodules with molecular tests guide extent of thyroid surgery 767 follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;120:3627–34.PubMedCrossRefGoogle Scholar
  95. 95.
    Nikiforov YE. Molecular analysis of thyroid tumors. Mod Pathol. 2011;24:534–44.CrossRefGoogle Scholar
  96. 96.
    Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.PubMedGoogle Scholar
  97. 97.
    Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95:625–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Ardighieri L, Zeppernick F, Hannibal CG, et al. Mutational analysis of BRAF and KRAS in ovarian atypical proliferative serous (borderline)tumors and associated peritoneal implants. J Pathol. 2014;232:16–22.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Hall A, Meyle KD, Lange MK, et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600E BRAF oncogene. Oncotarget. 2013;4:584–99.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Landau MS, Kuan SF, Chiosea S, et al. Braf-mutated microsatellite stable colorectal carcinoma: an aggressive adenocarcinoma with reduced CDX2 and increased cytokeratin 7 immunohistochemical expression. Hum Pathol. 2014;45:1704–12.PubMedCrossRefGoogle Scholar
  101. 101.
    Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90:6373–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Rodolico V, Cabibi D, Pizzolanti G, et al. BRAF V600E mutation and p27 kip1 expression in papillary carcinomas of the thyroid <1 cm and their paired lymph node metastases. Cancer. 2007;110:1218–26.PubMedCrossRefGoogle Scholar
  103. 103.
    Begum S, Rosenbaum E, Henrique R, et al. BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol. 2004;17:1359–63.PubMedCrossRefGoogle Scholar
  104. 104.
    Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004;202:247–51.PubMedCrossRefGoogle Scholar
  105. 105.
    Barollo S, Pezzani R, Cristiani A, et al. Prevalence, tumorigenic role, and biochemical implications of rare BRAF alterations. Thyroid. 2014;24:809–19.PubMedCrossRefGoogle Scholar
  106. 106.
    Santarpia L, Sherman SI, Marabotti A, et al. Detection and molecular characterization of a novel BRAF activated domain mutation in follicular variant of papillary thyroid carcinoma. Hum Pathol. 2009;40:827–33.PubMedCrossRefGoogle Scholar
  107. 107.
    Barzon L, Masi G, Merante Boschin I, et al. Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma. Eur J Endocrinol. 2008;159:77–80.PubMedCrossRefGoogle Scholar
  108. 108.
    Capper D, Preusser M, Habel A, et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 2001;122:11–9.CrossRefGoogle Scholar
  109. 109.
    Zimmermann AK, Camerisch U, Rechsteiner MP, et al. Value of immunohistochemistry in detection of BRAF V600E mutations in fine needle aspiration biopsies of papillary thyroid carcinoma. Cancer Cytopathol. 2014;122:48–58.PubMedCrossRefGoogle Scholar
  110. 110.
    Rossi ED, Martini M, Capodimonti S, et al. Analysis of immunocytochemical and molecular BRAF expression in thyroid carcinomas: a cyto-histological institutional experience. Cancer Cytopathol. 2014;122:527–35.PubMedCrossRefGoogle Scholar
  111. 111.
    Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990;4:1474–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Karga H, Lee JK, Vickery AL Jr, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab. 1991;73:832–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Hara H, Fulton N, Yashiro T, et al. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery. 1994;116:1010–6.PubMedGoogle Scholar
  114. 114.
    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;10:19–23.PubMedCrossRefGoogle Scholar
  115. 115.
    Ezzat S, Zheng L, Kolenda J, et al. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid. 1996;6:409–16.PubMedCrossRefGoogle Scholar
  116. 116.
    Vasko VV, Gaudart J, Allasia C, et al. Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma. Eur J Endocrinol. 2004;151:779–86.PubMedCrossRefGoogle Scholar
  117. 117.
    Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of Ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989;4:159–64.PubMedGoogle Scholar
  118. 118.
    Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three Ras genes in human thyroid tumors. Oncogene. 1990;5:565–70.PubMedGoogle Scholar
  119. 119.
    Esapa CT, Johnson SJ, Kendall-Taylor P, et al. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf). 1999;50:529–35.CrossRefGoogle Scholar
  120. 120.
    Nikiforov YE, Rowland JM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997;57:1690–4.PubMedGoogle Scholar
  121. 121.
    Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000;6:1093–103.PubMedGoogle Scholar
  122. 122.
    Fenton CL, Lukes Y, Nicholson D, et al. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab. 2000;85:1170–5.PubMedGoogle Scholar
  123. 123.
    Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science. 2000;289:1357–60.PubMedCrossRefGoogle Scholar
  124. 124.
    French CA, Alexander EK, Cibas ES, et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol. 2003;162:1053–60.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Dwight T, Thoppe SR, Foukakis T, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metabol. 2003;88:4440–5.CrossRefGoogle Scholar
  126. 126.
    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 Metabol. 2002;87:3947–52.Google Scholar
  127. 127.
    Mathur A, Weng J, Moses W. A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsies. Surgery. 2010;148:1176–7.CrossRefGoogle Scholar
  128. 128.
    Faquin W. Can a gene-expression classifier with high negative predictive value solve the indeterminate thyroid fine-needle aspiration dilemma? Cancer Cytopathol. 2013;121:403.CrossRefGoogle Scholar
  129. 129.
    Rossi ED, Larocca LM, Fadda G. The first line alternative methods to gene-expression classifier. Cancer Cytopathol. 2013;121:116–9.CrossRefGoogle Scholar
  130. 130.
    Rossi ED, Fadda G, Schmitt F. The nightmare of indeterminate follicular proliferations: when liquid-based cytology and ancillary techniques are not a moon landing but a realistic plan. Acta Cytol. 2014;58:543–51.PubMedCrossRefGoogle Scholar
  131. 131.
    Nikiforov YE, Ohori P, Hodack 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 Metabol. 2011;96:3390–7.CrossRefGoogle Scholar
  132. 132.
    Kelly LM, Barila G, Liu P, et al. Identification of the trasformin STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci USA. 2014;111:4233–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Ricarte-Filho JC, Li S, Garcia-Rendueles ME, et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest. 2013;123:4935–44.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Landa I, Ganly I, Chan TA, et al. Frequent somatic TERT promoter mutations in thyroid cancers: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab. 2013;98:E1562–6.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Liu X, Bishop J, Shan Y, et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 2013;20:603–10.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Melo M, Da Rocha AG, Vinagre J, et al. TERT promoter mutations are a major indicator of poor out come in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99:E754–65.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013;309:1493–501.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2015;33(1):42–50.PubMedCrossRefGoogle Scholar
  139. 139.
    Xing M, Liu R, Liu X, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 2014;32:2718–26.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Demeure MJ, Aziz M, Rosenberg R, et al. Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target. World J Surg. 2014;38:1296–305.PubMedCrossRefGoogle Scholar
  141. 141.
    Godbert Y, Henriques de Figueiredo B, Bonichon F, et al. Remarkable response to crizotinib in woman with anaplastic lymphoma kinase-rearranged anaplastic thyroid carcinoma. J Clin Oncol. 2015;33:e84–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Rossi ED, Morassi F, Santeusanio G, et al. Thyroid fine-needle aspiration cytology processed by Thin Prep: an additional slide decreased the number of inadequate results. Cytopathology. 2010;21:97–102.PubMedCrossRefGoogle Scholar
  143. 143.
    Rossi ED, Raffaelli M, Minimo C, et al. Immunocytochemical evaluation of thyroid neoplasms on thin-layer smears from fine-needle aspiration biopsies. Cancer. 2005;105:87–95.PubMedCrossRefGoogle Scholar
  144. 144.
    Cochand-Priollet B, Prat JJ, Polivka M, et al. Thyroid fine needle aspiration: the morphological features on ThinPrep slide preparations. Eighty cases with histological control. Cytopathol. 2003;14:343–9.CrossRefGoogle Scholar
  145. 145.
    Dabbs D, Abendroth CS, Grenko RT, et al. Immunocytochemistry on the thin-prep processor. Diagn Cytopathol. 1997;17:388–92.PubMedCrossRefGoogle Scholar
  146. 146.
    Cochand-Priollet B, Dahan H, Laloi-Michelin M, et al. Immunocytochemistry with cytokeratin 19 and HBME-1 increases the diagnostic accuracy of thyroid fine-needle aspirations. Preliminary report of 150 liquid-based fine needle aspirations with histological control. Thyroid. 2011;21:1067–73.PubMedCrossRefGoogle Scholar
  147. 147.
    Bizzarro T, Martini M, Marrocco C, et al. The role of CD56 in thyroid fine needle aspiration cytology: a pilot study performed on liquid based cytology. PloS One. 2015;17(10):e0132939.CrossRefGoogle Scholar
  148. 148.
    Niemeier LA, Kuffner Akatsu H, Song C, et al. A combined molecular-pathologic score improbe risk stratification of papillary micro carcinoma. Cancer. 2011;118:2069–77.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Collins J, Rossi ED, Chandra A, et al. Terminology and nomenclature schemes for reporting thyroid cytopathology: an overview. Sem Diagn Pathol. 2015;32:258–63.CrossRefGoogle Scholar
  150. 150.
    Chudova D, Wilde JI, Wang ET, et al. Molecular classification of thyroid nodules using high-dimensionality genomic data. J Clin Endocrinol Metab. 2010;95:5296–304.PubMedCrossRefGoogle Scholar
  151. 151.
    Keutgen XM, Filicori F, Fahey TJ. Molecular diagnosis for indeterminate thyroid nodules on fine needle aspiration. Advances and limitations. Exp Rev Mol Diagn. 2013;13:613–23.CrossRefGoogle Scholar
  152. 152.
    Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367:705–15.PubMedCrossRefGoogle Scholar
  153. 153.
    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;99:4069–77.PubMedCrossRefGoogle Scholar
  154. 154.
    Dedhia PH, Rubio GA, Cohen MS, et al. Potential effects of molecular testing of indeterminate thyroid nodule fine needle aspiration biopsy on thyroidectomy volume. World J Surg. 2014;38:634–8.PubMedCrossRefGoogle Scholar
  155. 155.
    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:E2297–306.PubMedCrossRefGoogle Scholar
  156. 156.
    Duick DS, Klopper JP, Diggans JC, et al. The impact of benign gene expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with indeterminate cytopathology. Thyroid. 2012;22:996–1001.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Li H, Robinson KA, Anton B, et al. Cost-effectiveness of a novel molecular test for cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011;96:1905–12.CrossRefGoogle Scholar
  158. 158.
    Wong KS, Angell TE, Strickland KC, et al. Noninvasive follicular variant of papillary thyroid carcinoma and the afirma gene-expression classifier. Thyroid. 2016;26:911–5.PubMedCrossRefGoogle Scholar
  159. 159.
    Ma T, Gostissa M, Altamura S, et al. Transcriptional activation of the cicli A gene by the architectural transcription factor HMGA2. Mol Cell Biol. 2003;23:9104–16.CrossRefGoogle Scholar
  160. 160.
    Jin L, Lloyd RV, Nassar A, et al. HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR. Diagn Mol Pathol. 2011;20:71–80.PubMedCrossRefGoogle Scholar
  161. 161.
    Guerriero E, Ferraro A, Desiderio D, et al. UbcH10 expression on thyroid fine-needle aspiration. Cancer Cytopathol. 2010;118:157–65.PubMedCrossRefGoogle Scholar
  162. 162.
    Wells SA, Asa SL, Dralle H, et al. The American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015;25:567–610.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Rossi ED, Raffaelli M, Mule A, et al. Relevance of immunocytochemistry on thin-layer cytology in thyroid lesions suspicious for medullary carcinoma: a case-control study. Appl Immunohistochem Mol Morphol. 2008;16:548–53.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab. 1959;19:152–61.PubMedCrossRefGoogle Scholar
  165. 165.
    Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MENtype 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–71.PubMedCrossRefGoogle Scholar
  166. 166.
    Tuttle RM, Ball DW, Byrd D, Daniels GH, et al. Medullary carcinoma. J Natl Compr Canc Netw. 2010;8:512–30.PubMedCrossRefGoogle Scholar
  167. 167.
    Kloos RT, Eng C, Evans DB, Francis GL, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565–612.PubMedCrossRefGoogle Scholar
  168. 168.
    Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42:581–8.PubMedCrossRefGoogle Scholar
  169. 169.
    Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73:278–81.PubMedCrossRefGoogle Scholar
  170. 170.
    Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrineneoplasia type 2. Clinics (Sao Paulo). 2012;61:69–75.CrossRefGoogle Scholar
  171. 171.
    Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15:1213–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Gimm O, Marsh DJ, Andrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82:3902–390.PubMedCrossRefGoogle Scholar
  173. 173.
    Mazeh H, Mizrahi I, Halle D, et al. Development of a microRNA-based molecular assay for the detection of papillary thyroid carcinoma in aspiration biopsy samples. Thyroid. 2011;21:111–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Shen R, Liyanarachchi S, Li W. MicroRNA signature in thyroid fine needle aspiration cytology applied to “atipia of undetermined significance” cases. Thyroid. et al., 2012;22:9–16.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Nikiforova MN, Chiosea SI, Nikiforov YE. MicroRNA expression profiles in thyroid microRNAs in thryoid fine needle aspiration biopsy samples. Thyroid. 2012;22:285–91.CrossRefGoogle Scholar
  176. 176.
    Nikiforova MN, Tseng GC, Steward D, et al. MicroRNA expression profiling of thyroid tumors: Biological significance and diagnistic utility. J Clin Endocrinol Metab. 2008;93:1600–8.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Mazeh H, Levy Y, Mizrahi I, et al. Differentiating benign from malignant thyroid nodules using micro ribonucleic acid amplification in residual cells obtained by fine needle aspiration biopsy. J Surg Res. 2013;180:216–21.PubMedCrossRefGoogle Scholar
  178. 178.
    Rossi ED, Martini M, Bizzarro T, et al. The evaluation of miRNAs on thyroid FNAC: the promising role of miR-375 in follicular neoplasms. Endocrine. 2016;54(3):723–32.PubMedCrossRefGoogle Scholar
  179. 179.
    Keutgen XM, Filicori F, Crowley MJ, et al. A panel of four miRNAs accurately differentiates malignant from benign indeterminate thyroid lesions on fine needle aspiration. Clin Cancer Res. 2012;18:2032–8.PubMedCrossRefGoogle Scholar
  180. 180.
    Pallante P, Visone R, Ferracin M, et al. MircoRNA deregulation in human thyroid papillary carcinomas. Endocr Rel Cancer. 2006;13:497–508.CrossRefGoogle Scholar
  181. 182.
    Weber F, Teresi RE, Broelsch CE, et al. A limited set of human microRNA is deregulated in follicular thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:3584–91.PubMedCrossRefGoogle Scholar
  182. 182.
    Tetzlaff MT, Liu A, Xu X, Master SR, et al. Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues. Endocr Pathol. 2007;18:163–73.PubMedCrossRefGoogle Scholar
  183. 183.
    Chen YT, Kitabayashi N, Zhou XK, et al. MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma. Mod Pathol. 2008;21:1139.46.PubMedGoogle Scholar
  184. 184.
    Sheu SY, Grabellus F, Schwertheim S, et al. Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumors. Br J Cancer. 2010;102:376–82.PubMedCrossRefGoogle Scholar
  185. 185.
    Peng Y, Li C, Luo DC, et al. Expression profile and clinical significance of microRNAs in papillary thyroid carcinoma. Molecules. 2014;19:11586–99.PubMedCrossRefGoogle Scholar
  186. 186.
    Chou CK, Chen RF, Chou FF, et al. MiR-146 is highly expressed in adult papillary thyroid carcinoma with high risk features including extrathyroidal invasion and the BRAF (V600E) mutation. Thyroid. 2010;20:489–94.PubMedCrossRefGoogle Scholar
  187. 187.
    Yip L, Kelly L, Shuai Y, et al. MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011;18:2035–41.PubMedCrossRefGoogle Scholar
  188. 188.
    Hudson J, Duncavage E, Tamburrino A, et al. Over expression of miR-10a and miR-375 and down regulation of YAP1 in medullary thyroid carcinoma. Exp Mol Pathol. 2013;95:62–7.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Yan JW, Lin JS, He XX. The emerging role of miR-375 in cancer. Int J Cancer. 2013;135:1011–8.PubMedCrossRefGoogle Scholar
  190. 190.
    Jikuzono T, Kawamoto M, Yoshitake H, et al. The miR-221/222 custer, miR-10B and Mir-92a are highly upregulated in metastatic minimally invasive follicular thyroid carcinoma. Int J Oncol. 2013;42:1858–68.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Agretti P, Ferrarini E, Rago T, et al. MicroRNA expression profile help to distinguish benign nodules from papillary thyroid carcinomas starting from cells of fine needle aspiration. Eur J Endocrinol. 2012;167:393–400.PubMedCrossRefGoogle Scholar
  192. 192.
    Zhang Y, Zhong Q, Chen X, et al. Diagnostic value of microRNAs in discriminating malignant thyroid nodules from benign ones on fine needle aspiration samples. Tumor Biol. 2014;35:9343–53.CrossRefGoogle Scholar
  193. 193.
    Dettmer M, Perren A, Moch H, et al. Comprehensive microRNA expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma. Thyroid. 2013;23:1383–9.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Dettmer M, Vogetseder A, Durso MB, et al. MicroRNA expression array identifies novel diagnostic markers for conventional and oncocytic follicular thyroid carcinomas. J Clin Endocrinol Metab. 2013;98:E1–7.PubMedCrossRefGoogle Scholar
  195. 195.
    Paskas S, Jankovic J, Zivalievic V, et al. Malignant risk stratification of thyroid FNA specimens with indeterminate cytology based on molecular testing. Cancer Cytopathol. 2015;123:471–9.PubMedCrossRefGoogle Scholar
  196. 196.
    Braun J, Hoang-Vu C, Dralle H, et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroidcarcinomas. Oncogene. 2010;29:4237–44.PubMedCrossRefGoogle Scholar
  197. 197.
    Kitano M, Rahbari R, Patterson EE, et al. Expression profiling of difficult-to-diagnose thyroid histological subtypes shows distinct expression profiles and identify candidate diagnostic miRNAs. Ann Surg Oncol. 2011;18:3443–52.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Fadda G, Rossi ED, Raffaelli M, et al. Follicular thyroid neoplasms can be classified as low and high risk according to HBME-1 and Galectin 3 expression on liquid based fine needle cytology. Eur J Endocrinol. 2011;165:447–53.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Anatomic Pathology and HistologyFondazione Universtaria Policlinico Agostino Gemelli-IRCCSRomeItaly
  2. 2.Service of Clinical PathologyLausanne University Hospital, Institute of PathologyLausanneSwitzerland

Personalised recommendations