Kronach, 3.5.2011

CRPPH Workshop Tokyo 21-23. 2. 2014-

Radiation and Thyroid Cancer

Chr.Reiners, Wuerzburg

Chr.Reiners, Universitätsklinikum WürzburgNational WHO-Collaboration Center - Radiation Emergency Preparedness Assistance NetworkHead: Prof.Dr.Chr.ReinersAffiliated toDepartment of Nuclear MedicineUniversity of Wuerzburg, GermanyDirector: Prof.Dr.A.Buck

Radiation Induced Thyroid Cancer

ISI Web of Science 15.02.14: 1702 Publications since 1950

1970 1980 1990 2000 2010

Radiation Induced Thyroid Cancer

Outline:

1. Thyroid Cancer Epidemiology Worldwide2. Radiation Exposure: Experiences of the Past3. The Chernobyl Reactor Accident4. Genetic Susceptibility

5. Clinical Presentation and Diagnosis6. Treatment and Prognosis

Thyroid Cancer Epidemiology Worldwide

IARC Cancer in Five Continents 2010

Age standardized incidence ratios 1980 - 2002

Females MalesScale factor x 2,5

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?

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

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 Endocrinologistsr=0.44, P=0.0031

Counts of Neck Ultrasonographyr=0.40, P=0.0091

Explaining 57% of the Variability in

State-Level Cancer Incidence

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?

Childhood Thyroid Cancer: US SEER 2008

Hogan et al J Surg Res 2009

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?

THYROID CANCER AFTER EXPOSURE TO IRRADIATION

Cohort and Screening Studies of Children

Study observ./expect. mean average excess cases dose relat.risk at 1Sv

Life Span Study (0-19y) 59 22.2 0.26 Sv 6.3 (95%CI: 5.1-10.1)

Israeli Tinea Capitis 43 10.7 0.1 Sv 34 (95%CI: 23-47)

Rochester Thymus 37 2.7 1.4 Sv 9.5 (95%CI: 6.9-12.7)

Lymphoid Hyperplasia 13 5.4 0.24 Sv 5.9 (95%CI: 1.8-11.8)

Michael Reese Tonsils 309 110.4 0.6 Sv 3.0 (95%CI: 2.6-3.5)

All 436 -- -- 4.4 (95%CI: 1.9-10.1)

E.Ron, Radiat.Res. 1995 significant

THYROID CANCER AFTER EXPOSURE TO IRRADIATION

The Life Span Study from Japanese A-Bomb Survivors

Study observ./expect. mean average excess cases dose relat.risk at 1Sv

All 132 94.3 0.26 Sv 1.5 (95%CI:0.5-2.1)

Sex male 22 14.9 0.27 Sv 1.80 female 110 79.4 0.26 Sv 1.49

Age at exposure 0-9 years 24 7.6 0.21 Sv 10.25 10-19 35 14.6 0.31 Sv 4.50 20-29 18 17.5 0.28 Sv 0.10

Thompson, Radiat.Res. 1994 significant

The New York Times 30.01.2014

Radiation Induced Thyroid Cancer: The Role of X –Ray and CT?

Daily Release of I-131, Te-132 and Cs-137 during 10 Days

after April 26 1986 at the Cernobyl NPP

Graphite-Fire

Activity Concentration of Cs-137 in Cows MilkActivity Concentration of Cs-137 in Cows MilkRovno, Ukraine 1988-2000Rovno, Ukraine 1988-2000

Permitted Level

Average Thyroid Doses per District after ChernobylAverage Thyroid Doses per District after Chernobyl

Demidchick 2003

0-4 Years

4-14 Years

> 14 Years

Thyroid Cancer Incidence in Children and AdolescentsThyroid Cancer Incidence in Children and Adolescents from Belarus after the Chernobyl Accidentfrom Belarus after the Chernobyl Accident

Basal Incidence0,5/100.000 (USA)

Additional Relative Risk for Thyroid Cancer in Different Additional Relative Risk for Thyroid Cancer in Different Age Groups after the Chernobyl Accident (Exposure 1Gy)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 exposureA

dddi

tiona

l rel

ativ

e ris

k

Increased Risk after > 0,1 Gy only in Children 0-17 years of age

Ivanov V.K. et al, Radiation Protection Dosimetry 2012

Post Chernobyl Cases and Baseline Incidence in Children Post Chernobyl Cases and Baseline Incidence in Children and Adolescents after the Chernobyl Accidentand Adolescents after the Chernobyl Accident

Jacob, Goulko et al Rad Res 2006

Belarus: Thyroid Cancer in Children and Adolescents

Tyro

id C

ance

rs C

ases

per

Yea

r

Observed cases

Spontaneous cases

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?

Nikiforov Y.E., Nikiforova M.N., Nat Rev Endocrinol 2011

Molecular Genetics of Thyroid Cancer

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

Molecular Genetics of Thyroid Cancer

FOXE1: Metaanalysis of Common Genetic Variants (SNP´s) and Differentiated Thyroid Cancer Risk

Hongling Zhu et al PLoS One 2013

Overall

FOXE1 is a Major Genetic Determinant for Radi-ation Related Thyroid Cancer after Chernobyl

Takahashi M et al Human Mol Genetics 2010

Radiation Induced Thyroid Cancer

Outline:

1. Thyroid Cancer Epidemiology Worldwide2. Radiation Exposure: Experiences of the Past3. The Chernobyl Reactor Accident4. Genetic Susceptibility

5. Clinical Presentation and Diagnosis6. Treatment and Prognosis

Diagnosis of Thyroid Cancer in Children by Diagnosis of Thyroid Cancer in Children by Gray Scale and Power-Doppler UltrasoundGray Scale and Power-Doppler Ultrasound

Lyshchik A, Drozd V, Demidchik Y, Reiners C Radiology 2005

Multivariate Logistic Regression

t-Value P

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

< 0.001

< 0.01

35 malignant, 68 benign nodules; mean age 14.2 + 2.7 years

Presentation, Treatment and Outcome of DTC in Children and Adolescents: Summary of the Literature 1987-2012

Reiners C. et al J Clin Endocrinol 2013

Presentation of DTC in Children and Adolescents: Summary of the Literature 1987-2012

Reiners C. et al J Clin Endocrinol 2013

Treatment of DTC in Children and Adolescents: Summary of the Literature 1987-2012

Reiners C. et al J Clin Endocrinol 2013

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)

1.Therapy 2/95 Activ. 6 GBq I-131Tg: 438 ng/ml

3.Therapy 12/95Cum. Activ. 18 GBq I-131Tg: 73 ng/ml

4.Therapy 7/96Cum. Activ. 24. 2 GBq I-131Tg: 2 ng/ml

G. A. * 05.02.1982, papillary DTC., pT4 N1b M1

Results of I-131 Therapy in 229 Childrenwith 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

Outcome of DTC in Children and Adolescents: Summary of the Literature 1987-2012

Reiners C. et al J Clin Endocrinol 2013

Acknowledgements

Prof.E.P.Demidchik †, Prof.Y.E.Demidchik,

Prof.V.M.Drozd, MinskSupported in part by the Federal Ministry of Radiation Protection

Dr.A.Lyshik, Minsk – Kyoto – Nashville

Prof.S.Yamashita, Nagasaki - Fukushima

Prof.V.A.Saenko, NagasakiSupported in part by the Nagasaki University 21st Century COE Program

Dr.J.Biko, Wuerzburg