1. Natural History of Thyroid Nodule Xiaohong Wu Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China

2. Thyroid Nodules: the scope of the problem Palpation: 3% ~ 7% Ultrasonography: 20% ~76% More common in: elderly persons; women; those with iodine deficiency; those with a history of radiation exposure. Endocr Pract. 2010;16(Suppl 1)

3. Prevalence of Thyroid Incidentalomas in health check-up ages(year)male/femalemale(%)female (%)total (%) 10 ~22/149.17.18.3 30 ~69/6117.423.020.0 50 ~86/5939.5 1) 52.5 3) 44.8 2) ≥7019/1073.7 1) 60.0 3) 69.0 2) total196/14431.636.133.5 Note: compared with other ages, 1) P < 0.01, 2) P <0.05, compared with group A 、 B, 3) P < 0.05 Wu X, Liu C, et al. Chinese Journal of Practical Internal Medicine ， 2005; 25(9):823-824

4. Prevalence of Thyroid Nodules in Jiangsu Province ages (year)malefemale sample size casesprevalencesample size casesprevalence 20-29242124.96273238.42 30-39386307.7771610915.22 40-495676311.11105619618.56 50-5961710517.02106132830.91 60-55213424.2865829444.68 total236434414.55376495025.24 Feng C, Liu C, et al. Chinese Journal of Endocrinology and Metabolism. 2011, 27: 492-494 In China, according to a recent community survey in ten cities, thyroid nodules have a prevalence of approximately 18.6%.

5. Etiology of Thyroid Nodules Endocr Rev. 2003;24(1):102-32.

6. Endocr Pract. 2010;16(Suppl 1)

7. Pat. P.M. Nodular Volume After 6 Years 3.1 ml4.3 ml 6.3 ml

8. Course of Thyroid Nodules What is the long-term course of thyroid nodules? What influences growth and function of thyroid nodules? Questions

9. Long-Term Follow-up of Thyroid Nodule Growth 109 euthyroid patients with benign thyroid nodules 95 women, 14 men; 46,2 ± 12,7 (14 - 73) years Follow-up of at least 3 years 3 - 13 years (median 4,9 years) Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

10. Development of Thyroid Nodules Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

11. Evaluation of Factors affecting Thyroid Nodules Growth Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

12. Evaluation of Factors affecting Thyroid Nodules Growth Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

13. Determinants of Nodular Growth According to the Cox Proportional Harzards Model There was no significant influence on the growth pattern of thyroid nodules of: – Age and sex of the patient, – Initial size of the nodule, – Scintigraphic behaviour of the nodule, – TSH-suppression by therapy Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

14. Conclusions The majority of benign thyroid nodules exhibits a slow growth rate during long-term observation. –After 3 yeras only half of the nodules have significantly increased in size. Thyroid nodules do grow more rapidly than the whole goitre of the same patient. The growth rate of thyroid nodules is mainly determined endogeneously rather than by exogenous factors, which show little, if any, infleunce. Quadbeck B, et al. Exp Clin Endocrinol Diabetes. 2002;110:348-354

15. How about Thyroid Incidentalomas Health check-up Thyroid ultrasonography Incidentalomas Clinical evaluation d>1cm, US-FNA FT3,FT4,TSH,Tg, Nodule volumes Follow-up n=323, M/F=196/144 n=144,M/F=62/52 Wu X, Liu C, et al. Chinese Journal of Practical Internal Medicine,2005;25(9):823-824

16. Four-year Follow-up of Thyroid Incidentalomas Wu X, Liu C, et al. Chinese Journal of Practical Internal Medicine,2005;25(9):823-824

17. Changes of Thyroid Incidentalomas after Four-year Follow-up Wu X, Liu C, et al. Chinese Journal of Practical Internal Medicine,2005;25(9):823-824

18. Characteristics of 20 included publications StudynamePublication yearStudy designFollow-upNodule nCriteria of changeChange of nodules at endpoint (percentage change) IncreaseNo changeDecrease Cheung1989Cohort1.5ys37NA19-- Kuma1994Cohort15ys134Not defined13.533.652.9 Knudsen2000Cohort2ys45Nodule diameter≥ 5mm 2.291.16.7 Buadbeck2000Cohort5ys57Not defined353124 Rago2001Cohort3ys27Nodule volume≥30%11.1-- Quadbeck2002Cohort3ys139Nodule volume≥30%61.215.823 Alexander2003Cohort20m330Nodule volume≥15%39-- Wu2005Cohort4ys100Nodule volume≥20%144046 Murat2006Cohort39m531Nodule volume≥15%3234.933.1 Gharib1987Case-control0.5y25Failure of any reduction 4060 Reverter1992Case-control1y20Nodule is not reduced or reduced to 50% 8515 Papini1993Case-control1y50Failure of any reduction 7426 La Rosa1995Case-control1y22Nodule is not reduced or reduced to 50% 1000 Mainini1995Case-control2ys10Nodule is not reduced or reduced to 50% 1000 Lima1997Case-control1y20Nodule is not reduced or reduced to 20% 8020 Papini1998Case-control5ys41Nodule is not reduced or reduced to 11.7% 53.746.3 Zelmanovitz1998Case-control1y24Nodule is not reduced or reduced to 50% 91.78.3 Larijani1999Case-control1y30Failure of any reduction 6040 Sakalauskiene2002Case-control0.5y25Failure of any reduction 8416 Wemeau2002Case-control1.5ys59Nodule is not reduced or reduced to 20% 69.530.5

19. Forest plot of 9 studies providing the percentage of volume increase for benign thyroid nodules

20. Forest plot of 6 studies providing rate of no-change of the volume for benign thyroid nodules

21. Forest plot of 17 publications providing rate of volume decrease for benign thyroid nodules

22. How about nodular goiter? On the basis of cross-sectional data and ultrasonic scanning, an average annual growth rate of 4.5% in multinodular goiter has been reported ---Am J Med 1990;89:602–608 In the Whickham survey, 20% of the women and 5% of the men who had goiters in the initial survey had no goiter in the follow-up survey, whereas only 4% of the women and none of the men acquired a goiter between the two surveys. ---Clin Endocrinol (Oxf) 1995;43:55–68 In a 20-yr follow-up study of 11- to 18-yr-old subjects in the southwestern United States, 60% of the 92 subjects who had diffuse goiters initially had spontaneous regression by the age of 30 yr. ---Am J Med 1991;91:363–370

23. Decreasing frequency of goiter with age A fall in lean body mass with age, known to be related to thyroid volume A fall with age in IGF-I and GH At least in women, the loss of estradiol-mediated increase in proliferation and down-regulation of the NIS gene Clin Endocrinol (Oxf) 1998;48:701–706 J Am Geriatr Soc 1999;47:1238–1243 Endocrinology 1999;140:5705–5711

24. Follow-up of Nontoxic Autonomously Functioning Thyroid Nodules J Clin Endocrinol Metab 1980;50:1089–1093

25. Correlation of change in nodule size and function and duration of follow up for nontoxic AFTN J Clin Endocrinol Metab 1980;50:1089–1093 Increase: 15/159=9.4% No change: 138/159=86.8% Decrease: 6/159=3.8% Toxic: 14/159=8.8%

26. Correlation of function of untreated AFTN with age after varying follow-up periods J Clin Endocrinol Metab 1980;50:1089–1093 Nodules greater than 3 cm in size at diagnosis carried a 20% risk of developing hyperthyroidism, whereas nodules less than 2.5 cm in size had only a 2-5% risk of developing hyperthyroidism within the same time frame

27. Correlation of changes in nodule size and function and duration of follow up for nontoxic AFTN from iodine-sufficient (control) and iodine-deficient (endemic) areas J Clin Endocrinol Metab 1983;56:283–287

28. Nontoxic Nodular Goiter An incidence of 8-10% of overt hyperthyroidism during a 6- to 12-yr follow-up period corresponding to 0-6% per year.. In part, this progression depends on genetic predisposition, somatic mutations in individual nodules, and extrinsic factors such as iodine intake. Postgrad Med J 1990;66:186–190 Clin Nucl Med 1979;4:181–190 J Clin Endocrinol Metab 1980;50:1089–1093 J Clin Endocrinol Metab 1983;56:283–287 Acta Endocrinol (Copenh) 1993;128:51–55

29. The natural history of thyroid nodule with respect to growth and function varies and is difficult to predict in a given patient. Most patients need no treatment after malignancy is ruled out. New molecular genetic techniques applied on FNAB should lead to an increasing understanding of the pathogenesis of nodular thyroid disease and a better characterization of phenotypes. Summary

30. Acknowledgements Yingyue Lv Yili Xu Xiaojing Wang Jiayu Zhu Xiaoyun Liu Huanhuan Chen Kuangfeng Xu Tao Yang Collaborators: Yu Duan Xinhua Ye Hongjun Lin Meiping Shen Wei Liu Supervisor: Chao Liu Grants: NSFC(30971404/C140406 and 81070621/H0704) Jiangsu Province key medical personnel project (RC2011068) International Science and technology cooperation (BZ2011042)