1. Kronach, 3.5.2011 CRPPH Workshop Tokyo 21-23. 2. 2014 - Radiation and Thyroid Cancer Chr.Reiners, Wuerzburg Chr.Reiners, Universitätsklinikum Würzburg National WHO-Collaboration Center - Radiation Emergency Preparedness Assistance Network Head: Prof.Dr.Chr.Reiners Affiliated to Department of Nuclear Medicine University of Wuerzburg, Germany Director: Prof.Dr.A.Buck

2. Radiation Induced Thyroid Cancer ISI Web of Science 15.02.14: 1702 Publications since 1950 1970 1980 1990 2000 2010

3. Radiation Induced Thyroid Cancer Outline: 1. Thyroid Cancer Epidemiology Worldwide 2. Radiation Exposure: Experiences of the Past 3. The Chernobyl Reactor Accident 4. Genetic Susceptibility 5. Clinical Presentation and Diagnosis 6. Treatment and Prognosis

4. Thyroid Cancer Epidemiology Worldwide IARC Cancer in Five Continents 2010 Age standardized incidence ratios 1980 - 2002 Females Males Scale factor x 2,5

5. Radiation Induced Thyroid Cancer Increasing Incidence – Questions: True increase of thyroid cancer incidence? Age dependancy of assumed increase? Radiation as possible carcinogen? Genetic fingerprint of radiation carcinogenesis?

6. US SEER Cancer Registry 2005: Thyroid 6 Chen et al. Cancer 2009 Incidence Females Males < 1,0 cm 1,0-2,9 cm 3,0-3,9 cm > 4,0 cm appr. 50% of the effect in tumors < 1,0cm

7. Epidemic of Thyroid Cancer in the US 2005-2009: Role of Endocrinologists and Ultrasound Udelsman & Zhang Thyroid 2013 Age Stand.Incidence Rate by State Density of Endocrinologists r=0.44, P=0.0031 Counts of Neck Ultrasonography r=0.40, P=0.0091 Explaining 57% of the Variability in State-Level Cancer Incidence

8. Radiation Induced Thyroid Cancer Increasing Incidence - Questions True increase of thyroid cancer incidence? Age dependancy of assumed increase? Radiation as possible carcinogen? Genetic fingerprint of radiation carcinogenesis?

9. Childhood Thyroid Cancer: US SEER 2008 Hogan et al J Surg Res 2009

10. Radiation Induced Thyroid Cancer Increasing Incidence – Questions True increase of thyroid cancer incidence? Age dependancy of assumed increase? Radiation as possible carcinogen? Genetic fingerprint of radiation carcinogenesis?

11. THYROID CANCER AFTER EXPOSURE TO IRRADIATION Cohort and Screening Studies of Children Studyobserv./expect.mean average excess cases dose relat.risk at 1Sv Life Span Study (0-19y)5922.20.26 Sv6.3 (95%CI: 5.1-10.1) Israeli Tinea Capitis4310.70.1 Sv34 (95%CI: 23-47) Rochester Thymus372.71.4 Sv9.5 (95%CI: 6.9-12.7) Lymphoid Hyperplasia135.40.24 Sv5.9 (95%CI: 1.8-11.8) Michael Reese Tonsils309110.40.6 Sv3.0 (95%CI: 2.6-3.5) All436----4.4 ( 95%CI: 1.9-10.1) E.Ron, Radiat.Res. 1995significant

12. THYROID CANCER AFTER EXPOSURE TO IRRADIATION The Life Span Study from Japanese A-Bomb Survivors Studyobserv./expect.mean average excess cases dose relat.risk at 1Sv All 13294.30.26 Sv1.5 (95%CI:0.5-2.1) Sex male2214.90.27 Sv1.80 female11079.40.26 Sv1.49 Age at exposure 0-9 years247.60.21 Sv10.25 10-193514.60.31 Sv4.50 20-291817.50.28 Sv0.10 Thompson, Radiat.Res. 1994significant

13. The New York Times 30.01.2014 Radiation Induced Thyroid Cancer: The Role of X –Ray and CT?

14. Daily Release of I-131, Te-132 and Cs-137 during 10 Days after April 26 1986 at the Cernobyl NPP Graphite-Fire

15. Activity Concentration of Cs-137 in Cows Milk Rovno, Ukraine 1988-2000 Permitted Level

16. Average Thyroid Doses per District after Chernobyl

17. Demidchick 2003 0-4 Years 4-14 Years > 14 Years Thyroid Cancer Incidence in Children and Adolescents from Belarus after the Chernobyl Accident from Belarus after the Chernobyl Accident Basal Incidence 0,5/100.000 (USA)

18. Additional Relative Risk for Thyroid Cancer in Different Age Groups after the Chernobyl Accident (Exposure 1Gy) P.Jacob et al Rad Res 2006 Age at the time of surgery Age at the time of exposure Addditional relative risk

19. Increased Risk after > 0,1 Gy only in Children 0-17 years of age Ivanov V.K. et al, Radiation Protection Dosimetry 2012

20. Post Chernobyl Cases and Baseline Incidence in Children and Adolescents after the Chernobyl Accident Jacob, Goulko et al Rad Res 2006 Belarus: Thyroid Cancer in Children and Adolescents Tyroid Cancers Cases per Year Observed cases Spontaneous cases

21. Radiation Induced Thyroid Cancer Increasing Incidence – Questions: True increase of thyroid cancer incidence? Age dependancy of assumed increase? Radiation as possible carcinogen? Genetic fingerprint of radiation carcinogenesis?

22. Nikiforov Y.E., Nikiforova M.N., Nat Rev Endocrinol 2011 Molecular Genetics of Thyroid Cancer

23. Nikiforov Y.E., Nikiforova M.N., Nat Rev Endocrinol 2011 Leerman –Neill R.J. et al Cancer 2013 Molecular Genetics of Thyroid Cancer

24. FOXE1: Metaanalysis of Common Genetic Variants (SNP´s) and Differentiated Thyroid Cancer Risk Hongling Zhu et al PLoS One 2013 Overall

25. FOXE1 is a Major Genetic Determinant for Radi- ation Related Thyroid Cancer after Chernobyl Takahashi M et al Human Mol Genetics 2010

26. Radiation Induced Thyroid Cancer Outline: 1. Thyroid Cancer Epidemiology Worldwide 2. Radiation Exposure: Experiences of the Past 3. The Chernobyl Reactor Accident 4. Genetic Susceptibility 5. Clinical Presentation and Diagnosis 6. Treatment and Prognosis

27. Diagnosis of Thyroid Cancer in Children by Gray Scale and Power-Doppler Ultrasound Lyshchik A, Drozd V, Demidchik Y, Reiners C Radiology 2005 Multivariate Logistic Regression t-ValueP Nodule size Hypoechogenicity Outline irregularity Subcapsular location Increased peri-/intranodular vascularisation 3.63 2.55 3.93 3.87 3.34 < 0.001 < 0.05 < 0.001 < 0.01 35 malignant, 68 benign nodules; mean age 14.2 + 2.7 years

28. Presentation, Treatment and Outcome of DTC in Children and Adolescents: Summary of the Literature 1987-2012 Reiners C. et al J Clin Endocrinol 2013

29. Presentation of DTC in Children and Adolescents: Summary of the Literature 1987-2012 Reiners C. et al J Clin Endocrinol 2013

30. Treatment of DTC in Children and Adolescents: Summary of the Literature 1987-2012 Reiners C. et al J Clin Endocrinol 2013

31. Histology 232 Papillary Cancers (99.1%) 2 Follicular Cancers ( 0.9%) Stage advanced pT1 5 pT2 75 pN0 7 pM0 134 pT3 4 pT4 150 pN1 227 pM1 100 (64%) (97 %) (42%) Reiners C. et al J Clin Endocrinol 2013 Children with Thyroid Cancer from Belarus (I-131-Treatment in Germany 04/1993 to 04/2012)

32. 1.Therapy 2/95 Activ. 6 GBq I-131 Tg: 438 ng/ml 3.Therapy 12/95 Cum. Activ. 18 GBq I-131 Tg: 73 ng/ml 4.Therapy 7/96 Cum. Activ. 24. 2 GBq I-131 Tg: 2 ng/ml G. A. * 05.02.1982, papillary DTC., pT4 N1b M1

33. Results of I-131 Therapy in 229 Children with Thyroid Cancer from Belarus 1993-2012 (134 M0 / 100 M1) Reiners C. et al J Clin Endocrinol 2013 1 cancer related case of death, 2 cases of recurrencies

34. Outcome of DTC in Children and Adolescents: Summary of the Literature 1987-2012 Reiners C. et al J Clin Endocrinol 2013

35. Acknowledgements Prof.E.P.Demidchik †, Prof.Y.E.Demidchik, Prof.V.M.Drozd, Minsk Supported in part by the Federal Ministry of Radiation Protection Dr.A.Lyshik, Minsk – Kyoto – Nashville Prof.S.Yamashita, Nagasaki - Fukushima Prof.V.A.Saenko, Nagasaki Supported in part by the Nagasaki University 21st Century COE Program Dr.J.Biko, Wuerzburg