Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Follicular cell-derived thyroid cancer

Nature Reviews Disease Primers volume 1, Article number: 15077 (2015) Cite this article

Subjects

Abstract

Follicular cell-derived thyroid cancers are derived from the follicular cells in the thyroid gland, which secrete the iodine-containing thyroid hormones. Follicular cell-derived thyroid cancers can be classified into papillary thyroid cancer (80–85%), follicular thyroid cancer (10–15%), poorly differentiated thyroid cancer (<2%) and undifferentiated (anaplastic) thyroid cancer (<2%), and these have an excellent prognosis with the exception of undifferentiated thyroid cancer. The advent and expansion of advanced diagnostic techniques has driven and continues to drive the epidemic of occult papillary thyroid cancer, owing to overdiagnosis of clinically irrelevant nodules. This transformation of the thyroid cancer landscape at molecular and clinical levels calls for the modification of management strategies towards personalized medicine based on individual risk assessment to deliver the most effective but least aggressive treatment. In thyroid cancer surgery, for instance, injuries to structures outside the thyroid gland, such as the recurrent laryngeal nerve in 2–5% of surgeries or the parathyroid glands in 5–10% of surgeries, negatively affect quality of life more than loss of the expendable thyroid gland. Furthermore, the risks associated with radioiodine ablation may outweigh the risks of persistent or recurrent disease and disease-specific mortality. Improvement in the health-related quality of life of survivors of follicular cell-derived thyroid cancer, which is decreased despite the generally favourable outcome, hinges on early tumour detection and minimization of treatment-related sequelae. Future opportunities include more widespread adoption of molecular and clinical risk stratification and identification of actionable targets for individualized therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Macroscopic appearance of the types and subtypes of follicular cell-derived thyroid cancer.
Figure 2: Sex-specific incidence and mortality rates for thyroid cancer by region.
Figure 3: Variability and trends in thyroid cancer incidence in women in countries with a high Human Development Index.
Figure 4: Signalling pathways involved in follicular cell-derived thyroid cancer development and progression.
Figure 5: Diagnosis of follicular-derived thyroid cancers.
Figure 6: Operative view of total thyroidectomy with en bloc central compartment dissection in node-positive papillary thyroid cancer.

Similar content being viewed by others

References

  1. World Health Organization. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs (eds DeLellis, R. A., Lloyd, R. V., Heitz, P. U. & Eng, C. ) 49–80 (IARC Press, 2004).

    Google Scholar 

  2. Nikiforov, Y. E. & Nikiforova, M. N. Molecular genetics and diagnosis of thyroid cancer. Nat. Rev. Endocrinol. 7, 569–580 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Jung, C. K. et al. The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. J. Clin. Endocrinol. Metab. 99, E276–E285 (2014). This study shows that the detection rate and the molecular profile of PTC have changed in the United States over the past three decades.

    Article  CAS  PubMed  Google Scholar 

  4. Albores-Saavedra, J., Henson, D. E., Glazer, E. & Schwartz, A. M. Changing patterns in the incidence and survival of thyroid cancer with follicular phenotype — papillary, follicular, and anaplastic: a morphological and epidemiological study. Endocr. Pathol. 18, 1–7 (2007).

    Article  PubMed  Google Scholar 

  5. Aschebrook-Kilfoy, B., Grogan, R. H., Ward, M. H., Kaplan, E. & Devesa, S. S. Follicular thyroid cancer incidence patterns in the United States, 1980–2009. Thyroid 23, 1015–1021 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lise, M. et al. Changes in the incidence of thyroid cancer between 1991 and 2005 in Italy: a geographical analysis. Thyroid 22, 27–34 (2012).

    Article  PubMed  Google Scholar 

  7. Ahn, H. S., Kim, H. J. & Welch, G. H. Korea's thyroid cancer “epidemic” — screening and overdiagnosis. N. Engl. J. Med. 371, 1765–1767 (2014). This paper clearly shows that PTC has been increasingly diagnosed in the past two decades because of increased imaging; this may have resulted in surgeries for insignificant lesions without benefit to patients.

    Article  PubMed  Google Scholar 

  8. Davies, L. & Welch, H. G. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295, 2164–2167 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Morris, L. G., Sikora, A. G., Tosteson, T. D. & Davies, L. The increasing incidence of thyroid cancer: the influence of access to care. Thyroid 23, 885–891 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Davies, L. & Welch, H. G. Current thyroid cancer trends in the United States. JAMA Otolaryngol. Head Neck Surg. 140, 317–322 (2014). By analysing nine surveillance, epidemiology and end results areas in the United States, the authors found that, during 1975–2009, the absolute increase in thyroid cancer in women was almost four-times greater than that of men, which is most likely due to higher diagnosis rates.

    Article  PubMed  Google Scholar 

  11. Hughes, D. T., Haymart, M. R., Miller, B. S., Gauger, P. G. & Doherty, G. M. The most commonly occurring papillary thyroid cancer in the United States is now a microcarinoma in a patient older than 45 years. Thyroid 21, 231–236 (2011).

    Article  PubMed  Google Scholar 

  12. Li, N., Du, X. L., Reitzel, L. R., Xu, L. & Sturgis, E. M. Impact of enhanced detection on the increase in thyroid cancer incidence in the United States: review of incidence trends by socioeconomic status within the surveillance, epidemiology, and end results registry, 1980–2008. Thyroid 23, 103–110 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Malone, M. K., Zagzag, J., Ogilvie, J. B., Patel, K. N. & Heller, K. S. Thyroid cancers detected by imaging are not necessarily small or early stage. Thyroid 24, 314–318 (2014).

    Article  PubMed  Google Scholar 

  14. Tuttle, R. M. et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 20, 1341–1349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ricarte-Filho, J. et al. Papillary thyroid carcinomas with cervical lymph node metastases can be stratified into clinically relevant prognostic categories using oncogenic BRAF, the number of nodal metastases, and extra-nodal extension. Thyroid 22, 575–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence and mortality and prevalence worldwide in 2012. IARC [online], (2013).

  17. United Nations Development Programme. Human Development Report 2013. The Rise of the South: Human Progress in a Diverse World (UNDP, 2013).

  18. Vaccarella, S. et al. The impact of diagnostic changes on the rise in thyroid cancer incidence: a population-based study in selected high-resource countries. Thyroid 25, 1127–1136 (2015). This study compares the number of new thyroid cancer cases by age group and time periods across countries to estimate the proportion of thyroid cancers that may be due to heightened surveillance of the thyroid gland.

    Article  PubMed  Google Scholar 

  19. La Vecchia, C. et al. Thyroid cancer mortality and incidence: a global overview. Int. J. Cancer 136, 2187–2195 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Neta, G. et al. A prospective study of medical diagnostic radiography and risk of thyroid cancer. Am. J. Epidemiol. 177, 800–809 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Franceschi, S. et al. The epidemiology of thyroid carcinoma. Crit. Rev. Oncog. 4, 25–52 (1993).

    CAS  PubMed  Google Scholar 

  22. Rinaldi, S. et al. Body size and risk of differentiated thyroid carcinomas: findings from the EPIC study. Int. J. Cancer 131, E1004–E1014 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Pellegriti, G. et al. Papillary thyroid cancer incidence in the volcanic area of Sicily. J. Natl Cancer Inst. 101, 1575–1583 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Brito, J. P., Morris, J. C. & Montori, V. M. Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumours. BMJ 347, f4706 (2013).

    Article  PubMed  Google Scholar 

  25. Giordano, T. J. et al. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014). This study provides comprehensive molecular characterization of PTC using various genomic, epigenetic and proteomic approaches.

    Article  CAS  PubMed Central  Google Scholar 

  26. Cohen, Y. et al. BRAF mutation in papillary thyroid carcinoma. J. Natl Cancer Inst. 95, 625–627 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Kimura, E. T. 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. 63, 1454–1457 (2003).

    CAS  PubMed  Google Scholar 

  28. Xing, M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12, 245–262 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Namba, H. et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 88, 4393–4397 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Nikiforova, M. N. et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab. 88, 5399–5404 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Ricarte-Filho, J. C. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 69, 4885–4893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Trovisco, V. et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J. Pathol. 202, 247–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Hou, P., Liu, D. & Xing, M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 6, 377–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Basolo, F. et al. Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases. J. Clin. Endocrinol. Metab. 95, 4197–4205 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Ciampi, R. et al. Oncogenic AKAP9–BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Invest. 115, 94–101 (2005). This study reports on the association between mutation type (point mutations and chromosomal rearrangements) and cancer aetiology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Namba, H., Rubin, S. A. & Fagin, J. A. Point mutations of Ras oncogenes are an early event in thyroid tumorigenesis. Mol. Endocrinol. 4, 1474–1479 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Suarez, H. G. et al. Presence of mutations in all three Ras genes in human thyroid tumors. Oncogene 5, 565–570 (1990).

    CAS  PubMed  Google Scholar 

  38. Karga, H. et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J. Clin. Endocrinol. Metab. 73, 832–836 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Manenti, G., Pilotti, S., Re, F. C., Della Porta, G. & Pierotti, M. A. Selective activation of Ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur. J. Cancer 30A, 987–993 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Ezzat, S., L. et al. Prevalence of activating Ras mutations in morphologically characterized thyroid nodules. Thyroid 6, 409–416 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Esapa, C. T., Johnson, S. J., Kendall-Taylor, P., Lennard, T. W. & Harris, P. E. Prevalence of Ras mutations in thyroid neoplasia. Clin. Endocrinol. (Oxf.) 50, 529–535 (1999).

    Article  CAS  Google Scholar 

  42. Motoi, N., et al. Role of Ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol. Res. Pract. 196, 1–7 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Adeniran, A. J. et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am. J. Surg. Pathol. 30, 216–222 (2006).

    Article  PubMed  Google Scholar 

  44. Santoro, M. et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J. Clin. Invest. 89, 1517–1522 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jhiang, S. M. et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137, 375–378 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Santoro, M. et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12, 1821–1826 (1996).

    CAS  PubMed  Google Scholar 

  47. Powell, D. J. Jr et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res. 58, 5523–5528 (1998).

    CAS  PubMed  Google Scholar 

  48. Nikiforov, Y. E. RET/PTC rearrangement in thyroid tumors. Endocr. Pathol. 13, 3–16 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Nikiforov, Y. E., Rowland, J. M., Bove, K. E., Monforte-Munoz, H. & Fagin, J. A. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 57, 1690–1694 (1997).

    CAS  PubMed  Google Scholar 

  50. Fenton, C. L. et al. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J. Clin. Endocrinol. Metab. 85, 1170–1175 (2000).

    CAS  PubMed  Google Scholar 

  51. Rabes, H. M. 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. 6, 1093–1103 (2000).

    CAS  PubMed  Google Scholar 

  52. Radice, P. et al. The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31. Oncogene 6, 2145–2148 (1991).

    CAS  PubMed  Google Scholar 

  53. Greco, A. et al. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene 7, 237–242 (1992).

    CAS  PubMed  Google Scholar 

  54. Miranda, C., Minoletti, F., Greco, A., Sozzi, G. & Pierotti, M. A. Refined localization of the human TPR gene to chromosome 1q25 by in situ hybridization. Genomics 23, 714–715 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Bongarzone, I. et al. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin. Cancer Res. 4, 223–228 (1998).

    CAS  PubMed  Google Scholar 

  56. Leeman-Neill, R. J. et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 120, 799–807 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Ricarte-Filho, J. C. et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J. Clin. Invest. 123, 4935–4944 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kelly, L. M. et al. Identification of the transforming STRN–ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc. Natl Acad. Sci. USA 111, 4233–4238 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kroll, T. G. et al. PAX8–PPARγ 1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289, 1357–1360 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Lui, W. O. et al. CREB3L2–PPARγ fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Res. 68, 7156–7164 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Dwight, T. et al. Involvement of the PAX8/peroxisome proliferator-activated receptor γ rearrangement in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 88, 4440–4445 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. French, C. A. et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am. J. Pathol. 162, 1053–1060 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nikiforova, M. N. et al. RAS point mutations and PAX8–PPARγ rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocrinol. Metab. 88, 2318–2326 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Armstrong, M. J. et al. PAX8/PPARγ rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. Thyroid 24, 1369–1374 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ito, T. et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res. 52, 1369–1371 (1992).

    CAS  PubMed  Google Scholar 

  66. Donghi, R. et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J. Clin. Invest. 91, 1753–1760 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fagin, J. A. et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J. Clin. Invest. 91, 179–184 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dobashi, Y. et al. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn. Mol. Pathol. 3, 9–14 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. Hou, P. et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin. Cancer Res. 13, 1161–1170 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Santarpia, L., El-Naggar, A. K., Cote, G. J., Myers, J. N. & Sherman, S. I. Phosphatidylinositol 3-kinase/Akt and Ras/Raf–mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 93, 278–284 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Kunstman, J. W. et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum. Mol. Genet. 24, 2318–2329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Landa, I. et al. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J. Clin. Endocrinol. Metab. 98, E1562–E1566 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu, T. et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 33, 4978–4984 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Liu, X. et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers.” Endocr. Relat. Cancer 20, 603–610 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Melo, M. et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 99, E754–E765 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Takahashi, K. et al. The presence of BRAF point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose. Mol. Carcinog. 46, 242–248 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Hamatani, K. et al. RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer Res. 68, 7176–7182 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Mizuno, T., Kyoizumi, S., Suzuki, T., Iwamoto, K. S. & Seyama, T. Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene 15, 1455–1460 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Mizuno, T. et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 19, 438–443 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Caudill, C. M., Zhu, Z., Ciampi, R., Stringer, J. R. & Nikiforov, Y. E. Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation. J. Clin. Endocrinol. Metab. 90, 2364–2369 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Nikiforova, M. N. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290, 138–141 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Roccato, E. et al. Proximity of TPR and NTRK1 rearranging loci in human thyrocytes. Cancer Res. 65, 2572–2576 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Gandhi, M., Medvedovic, M., Stringer, J. R. & Nikiforov, Y. E. Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. Oncogene 25, 2360–2366 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Richards, R. I. Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet. 17, 339–345 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Buttel, I., Fechter, A. & Schwab, M. Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann. NY Acad. Sci. 1028, 14–27 (2004).

    PubMed  Google Scholar 

  86. Gandhi, M., Dillon, L. W., Pramanik, S., Nikiforov, Y. E. & Wang, Y. H. DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells. Oncogene 29, 2272–2280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Guan, H. et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J. Clin. Endocrinol. Metab. 94, 1612–1617 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Romei, C. et al. Modifications in the papillary thyroid cancer gene profile over the last 15 years. J. Clin. Endocrinol. Metab. 97, E1758–E1765 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Huang, Y. et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc. Natl Acad. Sci. USA 98, 15044–15049 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chevillard, S. et al. Gene expression profiling of differentiated thyroid neoplasms: diagnostic and clinical implications. Clin. Cancer Res. 10, 6586–6597 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Frattini, M. et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene 23, 7436–7440 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Mazzanti, C. et al. Using gene expression profiling to differentiate benign versus malignant thyroid tumors. Cancer Res. 64, 2898–2903 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Giordano, T. J. et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 24, 6646–6656 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Finley, D. J., Arora, N., Zhu, B., Gallagher, L. & Fahey, T. J. 3rd. Molecular profiling distinguishes papillary carcinoma from benign thyroid nodules. J. Clin. Endocrinol. Metab. 89, 3214–3223 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Nikiforova, M. N., Tseng, G. C., Steward, D., Diorio, D. & Nikiforov, Y. E. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J. Clin. Endocrinol. Metab. 93, 1600–1608 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. He, H. et al. The role of microRNA genes in papillary thyroid carcinoma. Proc. Natl Acad. Sci. USA 102, 19075–19080 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pallante, P. et al. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr. Relat. Cancer 13, 497–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Mardente, S. et al. HMGB1 induces the overexpression of miR-222 and miR-221 and increases growth and motility in papillary thyroid cancer cells. Oncol. Rep. 28, 2285–2289 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Xing, M. Gene methylation in thyroid tumorigenesis. Endocrinology 148, 948–953 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Russo, D., Damante, G., Puxeddu, E., Durante, C. & Filetti, S. Epigenetics of thyroid cancer and novel therapeutic targets. J. Mol. Endocrinol. 46, R73–R81 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Fink, A., Tomlinson, G., Freeman, J. L., Rosen, I. B. & Asa, S. L. Occult micropapillary carcinoma associated with benign follicular thyroid disease and unrelated thyroid neoplasms. Mod. Pathol. 9, 816–820 (1996).

    CAS  PubMed  Google Scholar 

  102. Brignardello, E. et al. Ultrasound screening for thyroid carcinoma in childhood cancer survivors: a case series. J. Clin. Endocrinol. Metab. 93, 4840–4843 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Pacini, F. et al. Thyroid consequences of the Chernobyl nuclear accident. Acta Paediatr. Suppl. 88, 23–27 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Jacob, P., Kaiser, J. C. & Ulanovsky, A. Ultrasonography survey and thyroid cancer in the Fukushima Prefecture. Radiat. Environ. Biophys. 53, 391–401 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Michaelson, E. M. et al. Thyroid malignancies in survivors of Hodgkin lymphoma. Int. J. Radiat. Oncol. Biol. Phys. 88, 636–641 (2014).

    Article  PubMed  Google Scholar 

  106. Herraiz, M. et al. Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin. Gastroenterol. Hepatol. 5, 367–373 (2007).

    Article  PubMed  Google Scholar 

  107. Steinhagen, E. et al. The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized. Clin. Colorectal Cancer 11, 304–308 (2012).

    Article  PubMed  Google Scholar 

  108. Nose, V. Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv. Anatom. Pathol. 17, 428–436 (2010).

    Article  CAS  Google Scholar 

  109. Richards, M. L. Thyroid cancer genetics: multiple endocrine neoplasia type 2, non-medullary familial thyroid cancer, and familial syndromes associated with thyroid cancer. Surg. Oncol. Clin. N. Am. 18, 39–52 (2009).

    Article  PubMed  Google Scholar 

  110. Richards, M. L. Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid 20, 707–713 (2010).

    Article  PubMed  Google Scholar 

  111. Navas-Carrillo, D., Rios, A., Rodriguez, J. M., Parrilla, P. & Orenes-Pinero, E. Familial nonmedullary thyroid cancer: screening, clinical, molecular and genetic findings. Biochim. Biophys. Acta 1846, 468–476 (2014).

    CAS  PubMed  Google Scholar 

  112. Clark, O. H. Familial non medullary thyroid cancer. Acta Chirurgica Austriaca 34, 292 (2002).

    Article  Google Scholar 

  113. Nose, V. Familial follicular cell tumors: classification and morphological characteristics. Endocr. Pathol. 21, 219–226 (2010).

    Article  PubMed  Google Scholar 

  114. Oakley, G. M. et al. Increased melanoma risk in individuals with papillary thyroid carcinoma. JAMA Otolaryngol. Head Neck Surg. 140, 423–427 (2014).

    Article  PubMed  Google Scholar 

  115. Sadowski, S. M. et al. Prospective screening in familial nonmedullary thyroid cancer. Surgery 154, 1194–1198 (2013).

    Article  PubMed  Google Scholar 

  116. Oakley, G. M., Curtin, K., Pimentel, R., Buchmann, L. & Hunt, J. Establishing a familial basis for papillary thyroid carcinoma using the Utah Population Database. JAMA Otolaryngol. Head Neck Surg. 139, 1171–1174 (2013).

    Article  PubMed  Google Scholar 

  117. Rosario, P. W. et al. Ultrasonographic screening for thyroid cancer in siblings of patients with apparently sporadic papillary carcinoma. Thyroid 22, 805–808 (2012).

    Article  PubMed  Google Scholar 

  118. Reiners, C. Radioactivity and thyroid cancer. Hormones 8, 185–191 (2009).

    Article  PubMed  Google Scholar 

  119. Nagataki, S. & Nystrom, E. Epidemiology and primary prevention of thyroid cancer. Thyroid 12, 889–896 (2002).

    Article  PubMed  Google Scholar 

  120. Memon, A., Godward, S., Williams, D., Siddique, I. & Al-Saleh, K. Dental x-rays and the risk of thyroid cancer: a case–control study. Acta Oncol. 49, 447–453 (2010).

    Article  PubMed  Google Scholar 

  121. Journy, N. et al. Predicted cancer risks induced by computed tomography examinations during childhood, by a quantitative risk assessment approach. Radiat. Environ. Biophys. 53, 39–54 (2014).

    Article  PubMed  Google Scholar 

  122. Inskip, P. D. Thyroid cancer after radiotherapy for childhood cancer. Med. Pediatr. Oncol. 36, 568–573 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Becker, D. V. & Zanzonico, P. Potassium iodide for thyroid blockade in a reactor accident: administrative policies that govern its use. Thyroid 7, 193–197 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Franic´, Z. Iodine prophylaxis and nuclear accidents. Arh. Hig. Rada Toksikol. 50, 223–233 (1999).

  125. Braverman, E. R. et al. Managing terrorism or accidental nuclear errors, preparing for iodine-131 emergencies: a comprehensive review. Int. J. Environ. Res. Publ. Health 11, 7803–7804 (2014).

    Article  Google Scholar 

  126. Huszno, B. et al. Influence of iodine deficiency and iodine prophylaxis on thyroid cancer histotypes and incidence in endemic goiter area. J. Endocrinol. Invest. 26, 71–76 (2003).

    CAS  PubMed  Google Scholar 

  127. Clero, E. et al. Dietary iodine and thyroid cancer risk in French Polynesia: a case–control study. Thyroid 22, 422–429 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Liu, Z. T. & Lin, A. H. Dietary factors and thyroid cancer risk: a meta-analysis of observational studies. Nutr. Cancer 66, 1165–1178 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Minelli G., Conti, S., Manno, V., Olivieri, A. & Ascoli, V. The geographical pattern of thyroid cancer mortality between 1980 and 2009 in Italy. Thyroid 23, 1609–1618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Woodruff, S. L., Arowolo, O. A., Akute, O. O., Afolabi, A. O. & Nwariaku, F. Global variation in the pattern of differentiated thyroid cancer. Am. J. Surg. 200, 462–466 (2010).

    Article  PubMed  Google Scholar 

  131. Gyory, F. et al. Differentiated thyroid cancer and outcome in iodine deficiency. Eur. J. Surg. Oncol. 30, 325–331 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Franceschi, S. Iodine intake and thyroid carcinoma: a potential risk factor. Exp. Clin. Endocrinol. Diabetes 106, S38–S44 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. Knobel, M. & Medeiros-Neto, G. Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arq. Bras. Endocrinol. Metabol. 51, 701–712 (2007).

    Article  PubMed  Google Scholar 

  134. Sehestedt, T., Knudsen, N., Perrild, H. & Johansen, C. Iodine intake and incidence of thyroid cancer in Denmark. Clin. Endocrinol. (Oxf.) 65, 229–233 (2006).

    Article  CAS  Google Scholar 

  135. Xiao, Q., Park, Y., Hollenbeck, A. R. & Kitahara, C. M. Dietary flavonoid intake and thyroid cancer risk in the NIH-AARP diet and health study. Cancer Epidemiol. Biomarkers Prev. 23, 1102–1108 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cho, Y. A. & Kim, J. Thyroid cancer risk and smoking status: a meta-analysis. Cancer Causes Control 25, 1187–1195 (2014).

    Article  PubMed  Google Scholar 

  137. Pazaitou-Panayiotou, K., Polyzos, S. A. & Mantzoros, C. S. Obesity and thyroid cancer: epidemiologic associations and underlying mechanisms. Obes. Rev. 14, 1006–1022 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Fincham, S. M., Ugnat, A. M., Hill, G. B., Kreiger, N. & Mao, Y. Is occupation a risk factor for thyroid cancer? J. Occup. Environ. Med. 42, 318–322 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Dickman, P. W., Holm, L. E., Lundell, G., Boice J. D. Jr & Hall, P. Thyroid cancer risk after thyroid examination with 131I: a population-based cohort study in Sweden. Int. J. Cancer 106, 580–587 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Metzger, R. & Milas, M. Inherited cancer syndromes and the thyroid: an update. Curr. Opin. Oncol. 26, 51–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Milas, M. et al. Should patients with Cowden syndrome undergo prophylactic thyroidectomy? Surgery 152, 1201–1209 (2012).

    Article  PubMed  Google Scholar 

  142. Brito, J. P., Hay, I. D. & Morris, J. C. Low risk papillary thyroid cancer. BMJ 348, g3045 (2014).

    Article  PubMed  Google Scholar 

  143. Brito, J. P. & Davies, L. Is there really an increased incidence of thyroid cancer? Curr. Opin. Endocrinol. Diabetes Obes. 21, 405–408 (2014).

    Article  PubMed  Google Scholar 

  144. Cooper, D. S. et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009). This paper contains the 2009 comprehensive recommendations from the American thyroid Association for diagnosis and management of thyroid nodules and cancer. However, the 2015 guidelines are in press, and readers should have access by the time of publication of the present review.

    Article  PubMed  Google Scholar 

  145. Kim, D. S. et al. Sonographic features of follicular variant papillary thyroid carcinomas in comparison with conventional papillary thyroid carcinomas. J. Ultrasound Med. 28, 1685–1692 (2009).

    Article  PubMed  Google Scholar 

  146. Vidal-Casariego, A. et al. Accuracy of ultrasound elastography in the diagnosis of thyroid cancer in a low-risk population. Exp. Clin. Endocrinol. Diabetes 120, 635–638 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Cibas, E. S., Ali, S. Z. & NCI Thyroid FNA State of the Science Conference. The Bethesda system for reporting thyroid cytopathology. Am. J. Clin. Pathol. 132, 658–665 (2009).

    Article  PubMed  Google Scholar 

  148. Brito, J. P., Castro, M. R., Dean, D. S., Fatourechi, V. & Stan, M. Survey of current approaches to non-diagnostic fine-needle aspiration from solid thyroid nodules. Endocrine 49, 745–751 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Porterfield, J. R. et al. Reliability of benign fine needle aspiration cytology of large thyroid nodules. Surgery 144, 963–968 (2008).

    Article  PubMed  Google Scholar 

  150. Richmond, B. K. et al. False-negative results with the Bethesda system of reporting thyroid cytopathology: predictors of malignancy in thyroid nodules classified as benign by cytopathologic evaluation. Am. Surg. 80, 811–816 (2014).

    PubMed  PubMed Central  Google Scholar 

  151. Castro, M. R. et al. Predictors of malignancy in patients with cytologically suspicious thyroid nodules. Thyroid 21, 1191–1198 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Nikiforov, Y. 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 120, 3627–3634 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Alexander, E. K. et al. Multicenter clinical experience with the Afirma gene expression classifier. J. Clin. Endocrinol. Metab. 99, 119–125 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. McIver, B. et al. An independent study of a gene expression classifier (Afirma) in the evaluation of cytoologically indeterminate thyroid nodules. J. Clin. Endocrinol. Metab. 99, 4969–4977 (2014).

    Article  CAS  Google Scholar 

  155. Thomusch, O. et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 133, 180–185 (2003). References 152, 154 and 155 outline the newly developed molecular markers that are helpful in the management of indeterminate cytology obtained by FNA of thyroid nodules.

    Article  PubMed  Google Scholar 

  156. Dralle, H. et al. Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery. Surgery 136, 1310–1322 (2004).

    Article  PubMed  Google Scholar 

  157. Giordano, D. et al. Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature. Thyroid 22, 911–917 (2012). The rate of transient and permanent hypoparathyroidism was highest after bilateral central compartment node dissection compared to thyroidectomy with or without ipsilateral compartment dissection. The authors concluded that bilateral compartment dissection should be reserved for patients with node-positive PTC.

    Article  PubMed  Google Scholar 

  158. Dralle, H. & Machens, A. Surgical management of the lateral neck compartment for metastatic thyroid cancer. Curr. Opin. Oncol. 25, 20–26 (2013).

    Article  PubMed  Google Scholar 

  159. Machens, A., Holzhausen, H. J. & Dralle, H. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer 103, 2269–2273 (2005).

    Article  PubMed  Google Scholar 

  160. Londero, S. C. et al. Papillary thyroid microcarcinoma in Denmark 1996–2008: a national study of epidemiology and clinical significance. Thyroid 23, 1159–1164 (2013).

    Article  PubMed  Google Scholar 

  161. Mehanna, H. et al. Differences in the recurrence and mortality outcomes rates of incidental and nonincidental papillary thyroid microcarcinoma: a systematic review and meta-analysis of 21 329 person-years of follow-up. J. Clin. Endocrinol. Metab. 99, 2834–2843 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Arora, N. 3rd et al. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 19, 473–477 (2009).

    Article  PubMed  Google Scholar 

  163. Hay, I. D. et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 144, 980–987 (2008).

    Article  PubMed  Google Scholar 

  164. Mercante, G. et al. Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid 19, 707–716 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Lee, K. W., Cho, Y. J., Kim, J. G. & Lee, D. H. How many contralateral papillary thyroid carcinomas can be missed? World J. Surg. 37, 780–785 (2013).

    Article  PubMed  Google Scholar 

  166. Ito, Y. et al. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid 24, 27–34 (2014). This study shows that patients &gt;60 years of age can be candidates for observation instead of surgery.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Park, Y. J. et al. Papillary microcarcinoma in comparison with larger papillary thyroid carcinoma in BRAFV600E mutation, clinicopathological features, and immunohistochemical findings. Head Neck 32, 38–45 (2010).

    Article  PubMed  Google Scholar 

  168. Niemeier, L. A. et al. A combined molecular–pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer 118, 2069–2077 (2012).

    Article  CAS  PubMed  Google Scholar 

  169. Kuo, E. J., Goffredo, P., Sosa, J. A. & Roman, S. A. Aggressive variants of papillary thyroid microcarcinoma are associated with extrathyroidal spread and lymph-node metastases: a population-level analysis. Thyroid 23, 1305–1311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Machens, A. & Dralle, H. Correlation between the number of lymph node metastases and lung metastasis in papillary thyroid cancer. J. Clin. Endocrinol. Metab. 97, 4375–4382 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Vas Nunes, J. H. et al. Prognostic implications of lymph node yield and lymph node ratio in papillary thyroid carcinoma. Thyroid 23, 811–816 (2013).

    Article  PubMed  Google Scholar 

  172. Cho, S. Y. et al. Central lymph node metastasis in papillary thyroid microcarcinoma can be stratified according to the number, the size of metastatic foci, and the presence of desmoplasia. Surgery 157, 111–118 (2015).

    Article  PubMed  Google Scholar 

  173. Bardet, S. et al. Prognostic value of microscopic lymph node involvement in patients with papillary thyroid cancer. J. Clin. Endocrinol. Metab. 100, 132–140 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Conzo, G. et al. Impact of prophylactic central compartment neck dissection on locoregional recurrence of differentiated thyroid cancer in clinically node-negative patients: a retrospective study of a large clinical series. Surgery 155, 998–1005 (2014).

    Article  PubMed  Google Scholar 

  175. Wada, N. et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann. Surg. 237, 399–407 (2003).

    PubMed  PubMed Central  Google Scholar 

  176. Morris, L. G. T., Shaha, A. R., Tuttle, R. M., Sikora, A. G. & Ganly, I. Tall-cell variant of papillary thyroid carcinoma: a matched-pair analysis of survival. Thyroid 20, 153–158 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Regalbuto, C. et al. A diffuse sclerosing variant of papillary thyroid carcinoma: clinical and pathologic features and outcomes of 34 consecutive cases. Thyroid 21, 383–389 (2011).

    Article  PubMed  Google Scholar 

  178. Clain, J. B. et al. Extrathyroidal extension predicts extranodal extension in patients with positive lymph nodes: an important association that may affect clinical management. Thyroid 24, 951–957 (2014).

    Article  PubMed  Google Scholar 

  179. Ghossein, R. et al. Prognostic factors in papillary microcarcinoma with emphasis on histologic subtyping: a clinicopathologic study of 148 cases. Thyroid 24, 245–253 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Pacini, F. et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur. J. Endocrinol. 154, 787–803 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Dralle, H. et al. German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors. Langenbecks Arch. Surg. 398, 347–375 (2013).

    Article  PubMed  Google Scholar 

  182. Sancho, J. J., Lennard, T. W., Paunovic, I., Triponez, F. & Sitges-Serra, A. Prophylactic central neck dissection in papillary thyroid cancer: a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch. Surg. 399, 155–163 (2014). Concerning the rate of postsurgical complications and lymph node recurrences, the authors concluded that routine central compartment dissection should be risk-stratified according to tumour size, the age of the patient, multifocality, the presence or absence of lymph node metastases and the experience of the surgeon.

    Article  PubMed  Google Scholar 

  183. Iacobone, M., Jansson, S., Barczyn´ski, M. & Goretzki, P. Multifocal papillary thyroid carcinoma — a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch. Surg. 399, 141–154 (2014).

    Article  PubMed  Google Scholar 

  184. Dutenhefner, S. E. et al. BRAF: a tool in the decision to perform elective neck dissection? Thyroid 23, 1541–1546 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Viola, D. et al. Prophylactic central compartment lymph node dissection in papillary thyroid carcinoma. Clinical implications derived from the first prospective randomized controlled single institution study. J. Clin. Endocrinol. Metab. 100, 1316–1324 (2015).

    Article  CAS  PubMed  Google Scholar 

  186. Niederer-Wüst, S. M. et al. Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer. Surgery 157, 119–125(2015).

    Article  PubMed  Google Scholar 

  187. van Heerden, J. A. et al. Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery 112, 1130–1136 (1992).

    CAS  PubMed  Google Scholar 

  188. Dralle, H. & Machens, A. Surgical approaches in thyroid cancer and lymph-node metastases. Best Pract. Res. Clin. Endocrinol. Metab. 22, 971–987 (2008).

    Article  PubMed  Google Scholar 

  189. Asari, R. et al. Follicular thyroid carcinoma in an iodine-replete endemic goiter region: a prospectively collected, retrospectively analyzed clinical trial. Ann. Surg. 249, 1023–1031 (2009).

    Article  PubMed  Google Scholar 

  190. O'Neill, C. J. et al. Management of follicular thyroid carcinoma should be individualised based on degree of capsular and vascular invasion. Eur. J. Surg. Oncol. 37, 181–185 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Dionigi, G. et al. Minimally invasive follicular thyroid cancer (MIFTC) — a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch. Surg. 399, 165–184 (2014). Hemithyroidectomy instead of total thyroidectomy is favoured for patients with exclusive capsular without vascular invasion, who are &lt;45 years of age, with a tumour size of &lt;40 mm and are without metastases.

    Article  PubMed  Google Scholar 

  192. Kushchayeva, Y., Duh, Q. Y., Kebebew, E. & Clark, O. H. Prognostic indications for Hürthle cell cancer. World J. Surg. 28, 1266–1270 (2004).

    Article  PubMed  Google Scholar 

  193. Bishop, J. A., Wu, G., Tufano, R. P. & Westra, W. H. Histological patterns of locoregional recurrence in Hürthle cell carcinoma of the thyroid gland. Thyroid 22, 690–694 (2012).

    Article  PubMed  Google Scholar 

  194. Volante, M. et al. Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients. Cancer 100, 950–957 (2004).

    Article  PubMed  Google Scholar 

  195. Volante, M. et al. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am. J. Surg. Pathol. 31, 1256–1264 (2007).

    Article  PubMed  Google Scholar 

  196. Hiltzik, D. et al. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer 106, 1286–1295 (2006).

    Article  PubMed  Google Scholar 

  197. Ibrahimpasic, T. et al. Poorly differentiated thyroid carcinoma presenting with gross extrathyroidal extension: 1986–2009 Memorial Sloan-Kettering Cancer Center experience. Thyroid 23, 997–1002 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Smallridge, R. C. et al. American thyroid guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22, 1104–1139 (2012).

    Article  PubMed  Google Scholar 

  199. Besic, N. et al. Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur. J. Surg. Oncol. 27, 260–264 (2001).

    Article  CAS  PubMed  Google Scholar 

  200. Higashiyama, T. et al. Induction chemotherapy with weekly paclitaxel administration for anaplastic thyroid carcinoma. Thyroid 20, 7–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  201. Ito, K. et al. Multimodality therapeutic outcomes in anaplastic thyroid carcinoma: improved survival in subgroups of patients with localized primary tumors. Head Neck 34, 230–237 (2012).

    Article  PubMed  Google Scholar 

  202. Ross, D. S. et al. Recurrence after treatment of micropapillary thyroid cancer. Thyroid 19, 1043–1048 (2009).

    Article  PubMed  Google Scholar 

  203. Baudin, E. et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 83, 553–559 (1998).

    Article  CAS  PubMed  Google Scholar 

  204. Pacini, F. et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J. Clin. Endocrinol. Metab. 91, 926–932 (2006).

    Article  CAS  PubMed  Google Scholar 

  205. Schlumberger, M. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 372, 620–629 (2015).

    Article  CAS  Google Scholar 

  206. Mallick, U. et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N. Engl. J. Med. 366, 1674–1685 (2012).

    Article  CAS  PubMed  Google Scholar 

  207. Durante, C. et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J. Clin. Endocrinol. Metab. 91, 2892–2899 (2006).

    Article  CAS  PubMed  Google Scholar 

  208. Vaisman, F. et al. Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. Clin. Endocrinol. (Oxf.) 77, 132–138 (2012).

    Article  CAS  Google Scholar 

  209. Maloof, F., Vickery, A. L. & Rapp, B. An evaluation of various factors influencing the treatment of metastatic thyroid carcinoma with I131. J. Clin. Endocrinol. Metab. 16, 1–27 (1956).

    Article  CAS  PubMed  Google Scholar 

  210. Ichikawa, Y., Saito, E., Abe, Y., Homma, M. & Muraki, T. Presence of TSH receptor in thyroid neoplasms. J. Clin. Endocrinol. Metab. 42, 395–398 (1976).

    Article  CAS  PubMed  Google Scholar 

  211. Pacini, F. et al. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin. Endocrinol. (Oxf.) 23, 405–411 (1985).

    Article  CAS  Google Scholar 

  212. Pötter, E. et al. Western blot analysis of thyrotropin receptor expression in human thyroid tumors and correlation with TSH-binding. Biochem. Biophys. Res. Commun. 205, 361–367 (1994).

    Article  PubMed  Google Scholar 

  213. Sundram, F. et al. Well-differentiated epithelial thyroid cancer management in the Asia Pacific region: a report and clinical practice guideline. Thyroid 16, 461–469 (2006).

    Article  PubMed  Google Scholar 

  214. Pitoia, F. et al. Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer. Arq. Bras. Endocrinol. Metab. 53, 884–897 (2009).

    Article  Google Scholar 

  215. Pacini, F., Castagna, M. G., Brilli, L. & Pentheroudakis, G. Thyroid cancer: ESMO Clinical Practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 21 (Suppl. 5), v214–v219 (2010).

    Article  PubMed  Google Scholar 

  216. Dunhill, T. P. The Lettsomian Lectures: “The surgery of the thyroid gland”. Trans. Med. Soc. Lond. 60, 234–282 (1937).

    Google Scholar 

  217. Balme, H. W. Metastatic carcinoma of the thyroid successfully treated with thyroxine. Lancet 266, 812–813 (1954).

    Article  CAS  PubMed  Google Scholar 

  218. McGriff, N. J. et al. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann. Med. 34, 554–564 (2002).

    Article  CAS  PubMed  Google Scholar 

  219. Biondi, B. & Cooper, D. S. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 20, 135–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  220. Jonklaas, J. et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 16, 1229–1242 (2006).

    Article  PubMed  Google Scholar 

  221. Hovens, G. C. et al. Associations of serum thyrotropin concentrations with recurrence and death in differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 92, 2610–2615 (2007).

    Article  CAS  PubMed  Google Scholar 

  222. Sugitani, I. et al. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J. Surg. 34, 1222–1231 (2010).

    Article  PubMed  Google Scholar 

  223. Carhill, A. A. et al. Long-term outcomes following therapy in differentiated thyroid carcinoma: NTCTCS Registry analysis 1987–2012. J. Clin. Endocrinol. Metab. 100, 3270–3279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Sugitani, I. & Fujimoto, Y. Does postoperative thyrotropin suppression therapy truly decrease recurrence in papillary thyroid carcinoma? A randomized controlled trial. J. Clin. Endocrinol. Metab. 95, 4576–4583 (2010).

    Article  CAS  PubMed  Google Scholar 

  225. Tuttle, R. M. et al. Thyroid carcinoma. J. Natl Compr. Canc. Netw. 8, 1228–1274 (2010).

    Article  PubMed  Google Scholar 

  226. Haugen, B. R. & Sherman, S. I. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr. Rev. 34, 439–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Brose, M. S. et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, Phase 3 trial. Lancet 384, 319–328 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Blevins, D. P. et al. Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer. Thyroid 24, 918–922 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Leboulleux, S. et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, Phase 2 trial. Lancet Oncol. 13, 897–905 (2012).

    Article  CAS  PubMed  Google Scholar 

  230. Carr, L. L. et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin. Cancer Res. 16, 5260–5268 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Cabanillas, M. E., Brose, M. S., Holland, J., Ferguson, K. C. & Sherman, S. I. A Phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid 24, 1508–1514 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Bible, K. C. et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a Phase 2 consortium study. Lancet Oncol. 11, 962–972 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Schutz, F. A., Je, Y., Richards, C. J. & Choueiri, T. K. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J. Clin. Oncol. 30, 871–877 (2012).

    Article  CAS  PubMed  Google Scholar 

  234. Carhill, A. A. et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J. Clin. Endocrinol. Metab. 98, 31–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  235. Brose, M. S. et al. An open-label, multi-center Phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (ptc) positive for the BRAF V600 mutation and resistant to radioactive iodine (nct01286753, no25530). Eur. J. Cancer Abstr. 49, 28 (2013).

    Google Scholar 

  236. Kim, K. B. et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAFV600E mutation. Thyroid 23, 1277–1283 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Dadu, R. et al. Efficacy and tolerability of vemurafenib in patients with BRAFV600E-positive papillary thyroid cancer: M. D. Anderson Cancer Center off label experience. J. Clin. Endocrinol. Metab. 100, E77–E81 (2015).

    Article  CAS  PubMed  Google Scholar 

  238. Falchook, G. S. et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 25, 71–77 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Ho, A. L. et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623–632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Rothenberg, S. M., McFadden, D. G., Palmer, E. L., Daniels, G. H. & Wirth, L. J. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin. Cancer Res. 21, 1028–1035 (2015).

    Article  CAS  PubMed  Google Scholar 

  241. Sherman, S. I. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin. Oncol. (R. Coll. Radiol.) 22, 464–468 (2010).

    Article  CAS  Google Scholar 

  242. Shimaoka, K., Schoenfeld, D. A., DeWys, W. D., Creech, R. H. & DeConti, R. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56, 2155–2160 (1985).

    Article  CAS  PubMed  Google Scholar 

  243. Mazzaferri, E. L. & Jhiang, S. M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am. J. Med. 97, 418–428 (1994).

    Article  CAS  PubMed  Google Scholar 

  244. Lundgren, C. I., Hall, P. & Dickman, P. W. Influence of surgical and postoperative treatment on survival in differentiated thyroid cancer. Br. J. Surg. 94, 571–577 (2007).

    Article  CAS  PubMed  Google Scholar 

  245. Hay, I. D., McDougall, I. R. & Sisson, J. C. Perspective: the case against radioiodine remnant ablation in patients with well-differentiated thyroid carcinoma. J. Nucl. Med. 49, 1395–1397 (2008).

    Article  Google Scholar 

  246. Tagay, S. et al. Health-related quality of life, depression and anxiety in thyroid cancer patients. Qual. Life Res. 153, 755–763 (2005).

    CAS  Google Scholar 

  247. Dagan, T. et al. Quality of life of well-differentiated thyroid carcinoma patients. J. Laryngol. Otol. 118, 537–542 (2004).

    Article  PubMed  Google Scholar 

  248. Husson, O. et al. Health-related quality of life among thyroid cancer survivors: a systematic review. Clin. Endocrinol. (Oxf.) 75, 544–554 (2011). This article has outlined all of the HRQOL studies on thyroid cancer up to 2011.

    Article  Google Scholar 

  249. Davids, T., Witterick, I. J., Eski, S., Walfish, P. G. & Freeman, J. L. Three-week thyroxine withdrawal: a thyroid-specific quality of life study. Laryngoscope 116, 250–253 (2006).

    Article  PubMed  Google Scholar 

  250. Dow, K. H., Ferrell, B. R. & Anello, C. Quality-of-life changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy. Thyroid 7, 613–619 (1997).

    Article  CAS  PubMed  Google Scholar 

  251. Hoftijzer, H. et al. Quality of life in cured patients with differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 93, 200–203 (2008).

    Article  CAS  PubMed  Google Scholar 

  252. Hirsch, D. et al. Illness perception in patients with differentiated epithelial cell thyroid cancer. Thyroid 19, 459–465 (2009).

    Article  PubMed  Google Scholar 

  253. Husson, O. et al. Fatigue among short- and long-term thyroid cancer survivors: results from the population-based PROFILES registry. Thyroid 23, 1247–1255 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  254. Pelttari, H., Sintonen, H., Schalin-Jäntti, C. & Välimäki, M. J. Health-related quality of life in long-term follow-up of patients with cured TNM stage I or II differentiated thyroid carcinoma. Clin. Endocrinol. (Oxf.) 70, 493–497 (2009).

    Article  Google Scholar 

  255. Schultz, P. N., Stava, C. & Vassilopoulou-Sellin, R. Health profiles and quality of life of 518 survivors of thyroid cancer. Head Neck 25, 349–356 (2003).

    Article  PubMed  Google Scholar 

  256. Almeida, J., Vartanian, J. G. & Kowalski, L. P. Clinical predictors of quality of life in patients with initial differentiated thyroid cancers. Arch. Otolaryngol. Head Neck 135, 342–346 (2009).

    Article  Google Scholar 

  257. Botella-Carretero, J. I., Galan, J. M., Caballero, C., Sancho, J. & Escobar-Morreale, H. F. Quality of life and psychometric functionality in patients with differentiated thyroid carcinoma. Endocr. Relat. Cancer 10, 601–610 (2003).

    Article  CAS  PubMed  Google Scholar 

  258. Eustatia-Rutten, C. F. A. et al. Quality of life in long-term exogenous subclinical hyperthyroidism and the effect of restoration of euthyroidism, a randomized controlled trial. Clin. Endocrinol. (Oxf.) 64, 284–291 (2006).

    Article  CAS  Google Scholar 

  259. Husson, O. et al. Health-related quality of life and disease specific symptoms in long-term thyroid cancer survivors: a study from the population-based PROFILES registry. Acta Oncol. 52, 249–258 (2013). This is a large study that used a thyroid cancer-specific HRQOL questionnaire with long-term data.

    Article  PubMed  Google Scholar 

  260. Tan, L. G., Nan, L., Thumboo, J., Sundram, F. & Tan, L. K. Health-related quality of life in thyroid cancer survivors. Laryngoscope 117, 507–510 (2007).

    Article  PubMed  Google Scholar 

  261. Malterling, R. R. et al. Differentiated thyroid cancer in a Swedish county — long-term results and quality of life. Acta Oncol. 49, 454–459 (2010).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General, Visceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Ernst-Grube-Strasse 40, Halle, D-06097, Germany

    Henning Dralle & Andreas Machens

  2. Division of Surgical Oncology, Department of Surgery, University of Calgary, Calgary, Alberta, Canada

    Johanna Basa & Janice L. Pasieka

  3. Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

    Vahab Fatourechi & Ian D. Hay

  4. Infections and Cancer Epidemiology Group, International Agency for Research on Cancer, Lyon, France

    Silvia Franceschi

  5. Department of Pathology and Laboratory Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Yuri E. Nikiforov

  6. Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy

    Furio Pacini

  7. Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Steven I. Sherman

Authors
  1. Henning Dralle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Machens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johanna Basa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vahab Fatourechi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Silvia Franceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ian D. Hay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuri E. Nikiforov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Furio Pacini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Janice L. Pasieka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Steven I. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (H.D. and A.M.); Epidemiology (S.F.); Mechanisms/pathophysiology (Y.E.N.); Diagnosis, screening and prevention (I.D.H. and V.F.); Management (H.D., A.M., F.P. and S.I.S.); Quality of life (J.B. and J.L.P.); Outlook (F.P.); Overview of Primer (H.D.).

Corresponding author

Correspondence to Henning Dralle.

Ethics declarations

Competing interests

Y.E.N. declares that he has received consulting fees from Quest Diagnostics. S.I.S. declares that he has received consulting fees from Bayer, Eisai and Exelixis. All other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dralle, H., Machens, A., Basa, J. et al. Follicular cell-derived thyroid cancer. Nat Rev Dis Primers 1, 15077 (2015). https://doi.org/10.1038/nrdp.2015.77

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2015.77

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer