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.

  • Review Article
  • Published:

Thyroid nodule guidelines: agreement, disagreement and need for future research

Nature Reviews Endocrinology volume 7, pages 354–361 (2011)Cite this article

Subjects

Abstract

This article reviews agreement, disagreement and need for future research of the thyroid nodule guidelines published by the British Thyroid Association, National Cancer Institute, American Thyroid Association and the joint, transatlantic effort of three large societies, the American Society of Clinical Endocrinologists, Associazione Medici Endocrinologi and the European Thyroid Association, published in 2010. Consensus exists for most topics in the various guidelines. A few areas of disagreement, such as the use of scintigraphy, are mostly due to differences in disease prevalence in different countries. Most of the discordance, for example, on the use of calcitonin screening or fine-needle aspiration cytology classification, could probably be resolved by further expert discussions, as the basis is the same published evidence. Importantly, owing to a current lack of evidence in many areas, clinically very relevant areas of uncertainty need to be addressed by further research. This situation applies, for instance, to better definition of ultrasound malignancy criteria and the evaluation of emerging new diagnostic and therapeutic techniques, including molecular markers. For clinicians who advise individual patients, these areas of uncertainty can currently only be resolved by sound management on the basis of clinical judgment, experience and patient preference.

Key Points

  • Ultrasound should be performed in all patients with suspected or known thyroid nodules to confirm the presence of thyroid nodule(s) and to assess cancer risk

  • After cancer risk stratification, fine-needle aspiration (FNA) biopsy is the recommended diagnostic tool for patients with one or more clinically relevant thyroid nodules

  • FNA biopsy findings should be reported using a standard set of recommended diagnostic categories

  • The finding of benignity on FNA cytology is highly accurate and signals a very low false-negative rate

  • Many solitary benign thyroid nodules should be treated conservatively, without any further intervention

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: Clinical, radiologic and molecular variables that influence the estimated thyroid cancer risk of a nodule >1 cm in diameter.9,15,19,21,61,62

Similar content being viewed by others

References

  1. Guidelines for the managment of thyroid cancer. British Thyroid Association http://www.british-thyroid-association.org/news/Docs/Thyroid_cancer_guidelines_2007.pdf (2007).

  2. 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  Google Scholar 

  3. Pitman, M. B. et al. Techniques for thyroid FNA: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn. Cytopathol. 36, 407–424 (2008).

    Article  Google Scholar 

  4. Camargo, R. et al. Latin American Thyroid Association recommendations for the management of thyroid nodules. Arq. Bras. Endocrinol. Metabol. 53, 1167–1175 (2009).

    Article  Google Scholar 

  5. Wemeau, J.-L. et al. Recommandations pour la prise en charge des nodules thyroïdiens [French]. La Presse Medicale (in press).

  6. 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).

    Article  Google Scholar 

  7. Gharib, H. et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr. Pract. 16 (Suppl. 1), 1–43 (2010).

    Article  Google Scholar 

  8. Gharib, H., Papini, E. & Paschke, R. Thyroid nodules: a review of current guidelines, practices, and prospects. Eur. J. Endocrinol. 159, 493–505 (2008).

    Article  CAS  Google Scholar 

  9. Boelaert, K. et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J. Clin. Endocrinol. Metab. 91, 4295–4301 (2006).

    Article  CAS  Google Scholar 

  10. Cheung, K., Roman, S. A., Wang, T. S., Walker, H. D. & Sosa, J. A. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J. Clin. Endocrinol. Metab. 93, 2173–2180 (2008).

    Article  CAS  Google Scholar 

  11. Costante, G., Durante, C., Francis, Z., Schlumberger, M. & Filetti, S. Determination of calcitonin levels in C-cell disease: clinical interest and potential pitfalls. Nat. Clin. Pract. Endocrinol. Metab. 5, 35–44 (2009).

    Article  CAS  Google Scholar 

  12. Elisei, R. et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J. Clin. Endocrinol. Metab. 89, 163–168 (2004).

    Article  CAS  Google Scholar 

  13. Bonavita, J. A. et al. Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules can be left alone? AJR Am. J. Roentgenol. 193, 207–213 (2009).

    Article  Google Scholar 

  14. Frates, M. C. et al. Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J. Clin. Endocrinol. Metab. 91, 3411–3417 (2006).

    Article  CAS  Google Scholar 

  15. Kim, E. K. et al. New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid. AJR Am. J. Roentgenol. 178, 687–691 (2002).

    Article  Google Scholar 

  16. Kumar, H. et al. Gender, clinical findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology. Thyroid 9, 1105–1109 (1999).

    Article  CAS  Google Scholar 

  17. Moon, W. J. et al. Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study. Radiology 247, 762–770 (2008).

    Article  Google Scholar 

  18. Papini, E. et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J. Clin. Endocrinol. Metab. 87, 1941–1946 (2002).

    Article  CAS  Google Scholar 

  19. Ippolito, A. M. et al. Neural network analysis for evaluating cancer risk in thyroid nodules with an indeterminate diagnosis at aspiration cytology: identification of a low-risk subgroup. Thyroid 14, 1065–1071 (2004).

    Article  Google Scholar 

  20. Leenhardt, L. et al. Selection of patients with solitary thyroid nodules for operation. Eur. J. Surg. 168, 236–241 (2002).

    Article  Google Scholar 

  21. Okamoto, T. et al. Test performances of three diagnostic procedures in evaluating thyroid nodules: physical examination, ultrasonography and fine needle aspiration cytology. Endocr. J. 41, 243–247 (1994).

    Article  CAS  Google Scholar 

  22. Rago, T., Santini, F., Scutari, M., Pinchera, A. & Vitti, P. Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules. J. Clin. Endocrinol. Metab. 92, 2917–2922 (2007).

    Article  CAS  Google Scholar 

  23. Cosgrove, D. Future prospects for SonoVue and CPS. Eur. Radiol. 14 (Suppl. 8), P116–P124 (2004).

    PubMed  Google Scholar 

  24. Laurberg, P., Pedersen, K. M., Vestergaard, H. & Sigurdsson, G. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J. Intern. Med. 229, 415–420 (1991).

    Article  CAS  Google Scholar 

  25. Krohn, K. et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr. Rev. 26, 504–524 (2005).

    Article  CAS  Google Scholar 

  26. Sandrock, D., Olbricht, T., Emrich, D., Benker, G. & Reinwein, D. Long-term follow-up in patients with autonomous thyroid adenoma. Acta Endocrinol. (Copenh.) 128, 51–55 (1993).

    Article  CAS  Google Scholar 

  27. Zhang, S. et al. Thin core needle biopsy crush preparations in conjunction with fine-needle aspiration for the evaluation of thyroid nodules: a complementary approach. Cancer 114, 512–518 (2008).

    Article  Google Scholar 

  28. Danese, D., Sciacchitano, S., Farsetti, A., Andreoli, M. & Pontecorvi, A. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid 8, 15–21 (1998).

    Article  CAS  Google Scholar 

  29. Yang, J., Schnadig, V., Logrono, R. & Wasserman, P. G. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 111, 306–315 (2007).

    Article  Google Scholar 

  30. Yassa, L. et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer 111, 508–516 (2007).

    Article  Google Scholar 

  31. Castro, M. R., Caraballo, P. J. & Morris, J. C. Effectiveness of thyroid hormone suppressive therapy in benign solitary thyroid nodules: a meta-analysis. J. Clin. Endocrinol. Metab. 87, 4154–4159 (2002).

    Article  CAS  Google Scholar 

  32. Richter, B., Neises, G. & Clar, C. Pharmacotherapy for thyroid nodules. A systematic review and meta-analysis. Endocrinol. Metab. Clin. North Am. 31, 699–722 (2002).

    Article  Google Scholar 

  33. Zelmanovitz, F., Genro, S. & Gross, J. L. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses. J. Clin. Endocrinol. Metab. 83, 3881–3885 (1998).

    CAS  PubMed  Google Scholar 

  34. Goellner, J. R., Gharib, H., Grant, C. S. & Johnson, D. A. Fine needle aspiration cytology of the thyroid, 1980 to 1986. Acta Cytol. 31, 587–590 (1987).

    CAS  PubMed  Google Scholar 

  35. Kini, S. R. Thyroid Cytopathology: an Atlas and Text 17–26 (Lippincott Williams & Wilkins, Philadelphia, 2008).

    Google Scholar 

  36. Eszlinger, M. et al. Perspectives for improved and more accurate classification of thyroid epithelial tumors. J. Clin. Endocrinol. Metab. 93, 3286–3294 (2008).

    Article  CAS  Google Scholar 

  37. Eszlinger, M. & Paschke, R. Molecular fine-needle aspiration biopsy diagnosis of thyroid nodules by tumor specific mutations and gene expression patterns. Mol. Cell Endocrinol. 322, 29–37 (2010).

    Article  CAS  Google Scholar 

  38. Nikiforova, M. N. & Nikiforov, Y. E. Molecular diagnostics and predictors in thyroid cancer. Thyroid 19, 1351–1361 (2009).

    Article  CAS  Google Scholar 

  39. Freitas, B. C. & Cerutti, J. M. Genetic markers differentiating follicular thyroid carcinoma from benign lesions. Mol. Cell Endocrinol. 321, 77–85 (2010).

    Article  CAS  Google Scholar 

  40. Gharib, H. & Papini, E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol. Metab. Clin. North Am. 36, 707–735 (2007).

    Article  CAS  Google Scholar 

  41. Wesche, M. F., Tiel-V Buul, M. M., Lips, P., Smits, N. J. & Wiersinga, W. M. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J. Clin. Endocrinol. Metab. 86, 998–1005 (2001).

    Article  CAS  Google Scholar 

  42. Surks, M. I. et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291, 228–238 (2004).

    Article  CAS  Google Scholar 

  43. Fast, S., Bonnema, S. J. & Hegedüs, L. The majority of Danish nontoxic goitre patients are ineligible for Levothyroxine suppressive therapy. Clin. Endocrinol. (Oxf.) 69, 653–658 (2008).

    Article  Google Scholar 

  44. Hegedüs, L. Clinical practice. The thyroid nodule. N. Engl. J. Med. 351, 1764–1771 (2004).

    Article  Google Scholar 

  45. Nygaard, B., Hegedüs, L., Nielsen, K. G., Ulriksen, P. & Hansen, J. M. Long-term effect of radioactive iodine on thyroid function and size in patients with solitary autonomously functioning toxic thyroid nodules. Clin. Endocrinol. (Oxf.) 50, 197–202 (1999).

    Article  CAS  Google Scholar 

  46. Nygaard, B. et al. Radioiodine treatment of multinodular non-toxic goitre. BMJ 307, 828–832 (1993).

    Article  CAS  Google Scholar 

  47. Bonnema, S. J. et al. Improvement of goiter volume reduction after 0.3 mg recombinant human thyrotropin-stimulated radioiodine therapy in patients with a very large goiter: a double-blinded, randomized trial. J. Clin. Endocrinol. Metab. 92, 3424–3428 (2007).

    Article  CAS  Google Scholar 

  48. Nielsen, V. E., Bonnema, S. J., Jørgensen, H. B., Grupe, P. & Hegedüs, L. Stimulation with 0,3 mg recombinant human thyrotropin (rhTSH) increases the effect of 131I therapy in patients with nontoxic nodular goiter. A prospective, randomized, double-blind trial--secondary publication. Ugeskr. Laeger 168, 4098–4101 (2006).

    PubMed  Google Scholar 

  49. Fast, S. et al. Recombinant human thyrotropin-stimulated radioiodine therapy of nodular goiter allows major reduction of the radiation burden with retained efficacy. J. Clin. Endocrinol. Metab. 95, 3719–3725 (2010).

    Article  CAS  Google Scholar 

  50. Bennedbaek, F. N. & Hegedüs, L. Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J. Clin. Endocrinol. Metab. 88, 5773–5777 (2003).

    Article  CAS  Google Scholar 

  51. Valcavi, R. & Frasoldati, A. Ultrasound-guided percutaneous ethanol injection therapy in thyroid cystic nodules. Endocr. Pract. 10, 269–275 (2004).

    Article  Google Scholar 

  52. Verde, G. et al. Ultrasound guided percutaneous ethanol injection in the treatment of cystic thyroid nodules. Clin. Endocrinol. (Oxf.) 41, 719–724 (1994).

    Article  CAS  Google Scholar 

  53. Bennedbaek, F. N., Nielsen, L. K. & Hegedüs, L. Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: a randomized trial. J. Clin. Endocrinol. Metab. 83, 830–835 (1998).

    Article  CAS  Google Scholar 

  54. Lippi, F. et al. Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J. Clin. Endocrinol. Metab. 81, 3261–3264 (1996).

    CAS  PubMed  Google Scholar 

  55. Livraghi, T. et al. Treatment of autonomous thyroid nodules with percutaneous ethanol injection: 4-year experience. Radiology 190, 529–533 (1994).

    Article  CAS  Google Scholar 

  56. Papini, E. et al. Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid 17, 229–235 (2007).

    Article  CAS  Google Scholar 

  57. Døssing, H., Bennedbaek, F. N. & Hegedüs, L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules—a randomised study. Eur. J. Endocrinol. 152, 341–345 (2005).

    Article  Google Scholar 

  58. Døssing, H., Bennedbaek, F. N. & Hegedüs, L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid 16, 763–768 (2006).

    Article  Google Scholar 

  59. Valcavi, R., Riganti, F., Bertani, A., Formisano, D. & Pacella, C. M. Percutaneous laser ablation of cold benign thyroid nodules: a 3-year follow-up study in 122 patients. Thyroid 20, 1253–1261 (2010).

    Article  CAS  Google Scholar 

  60. Spiezia, S. et al. Thyroid nodules and related symptoms are stably controlled two years after radiofrequency thermal ablation. Thyroid 19, 219–225 (2009).

    Article  Google Scholar 

  61. Kwak, J. Y. et al. The role of ultrasound in thyroid nodules with a cytology reading of “suspicious for papillary thyroid carcinoma”. Thyroid 18, 517–522 (2008).

    Article  Google Scholar 

  62. Schlinkert, R. T. et al. Factors that predict malignant thyroid lesions when fine-needle aspiration is “suspicious for follicular neoplasm”. Mayo Clin. Proc. 72, 913–916 (1997).

    Article  CAS  Google Scholar 

  63. Alexander, E. K. Approach to the patient with a cytologically indeterminate thyroid nodule. J. Clin. Endocrinol. Metab. 93, 4175–4182 (2008).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Endokrinologie und Nephrologie, Universität Leipzig, Liebigstraße 20, D-04103, Leipzig, Germany

    Ralf Paschke

  2. Department of Endocrinology and Metabolism, Odense University Hospital, Kloevervaenget 6, DK-5000, Odense, Denmark

    Laszlo Hegedüs

  3. Division of Endocrinology, Thyroid Unit, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, MA, USA

    Erik Alexander

  4. Arcispedale Santa Maria Nuova, Viale Risorgimento 80, 42100, Reggio Emilia, Italy

    Roberto Valcavi

  5. Endocrinology and Metabolism Unit, Regina Apostolorum Hospital, Via San Francesco 50, Albano, 00041, Rome, Italy

    Enrico Papini

  6. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 1st Street Southwest, Rochester, 55905, MN, USA

    Hossein Gharib

Authors
  1. Ralf Paschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laszlo Hegedüs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberto Valcavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Enrico Papini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hossein Gharib
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to researching data for the article, a substantial contribution to discussion of content, writing and review/editing of the manuscript before submission.

Corresponding author

Correspondence to Ralf Paschke.

Ethics declarations

Competing interests

R. Paschke declares an association with the following companies: Merck (speakers bureau), Sanofi-aventis (speakers bureau). L. Hegedüs declares associations with the following company: Genzyme (consultant, speakers bureau, grant/research support). E. Alexander declares an association with the following company: Veracyte (grant/research support). The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paschke, R., Hegedüs, L., Alexander, E. et al. Thyroid nodule guidelines: agreement, disagreement and need for future research. Nat Rev Endocrinol 7, 354–361 (2011). https://doi.org/10.1038/nrendo.2011.1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing