3rd International Course3rd International CourseMultidisciplinary Approach on Thyroid Gland and Multidisciplinary Approach on Thyroid Gland and Oral Cavity CarcinomaOral Cavity CarcinomaZagreb – Croatia, September, 1st - 3rd, 2005Zagreb – Croatia, September, 1st - 3rd, 2005

THE INCREASING INCIDENCE OFTHE INCREASING INCIDENCE OFTHYROID CANCER IN CROATIA THYROID CANCER IN CROATIA COINCIDING WITH CHERNOBYL COINCIDING WITH CHERNOBYL NUCLEAR CATASTROPHENUCLEAR CATASTROPHE

Radetić, M., Kovačić, M., Parazajder, D., Radetić, Ma.,Radetić, M., Kovačić, M., Parazajder, D., Radetić, Ma.,Špoler Čanić, K.*Špoler Čanić, K.*

OTOLARYNGOLOGY & HEAD AND NECK SURGERY DEPARTMENT, OTOLARYNGOLOGY & HEAD AND NECK SURGERY DEPARTMENT, GENERAL HOSPITAL “SVETI DUH”, ZAGREB, CROATIAGENERAL HOSPITAL “SVETI DUH”, ZAGREB, CROATIA *THE STATE HYDROMETEOROLOGICAL INSTITUTE OF REPUBLIC OF*THE STATE HYDROMETEOROLOGICAL INSTITUTE OF REPUBLIC OF CROATIA, ZAGREB, CROATIACROATIA, ZAGREB, CROATIA

During the accident atDuring the accident at Chernobyl nuclear powerChernobyl nuclear power plant, on April 26th 1986,plant, on April 26th 1986, about 100 MCi of short-about 100 MCi of short-livedlived radioiodinesradioiodines

(I(I--132132,,133133,,135135) ) and 40and 40 MCiMCi

ofof I I--131131 were released intowere released into the atmospherethe atmosphere

The main zones of soil contaminations were to the west,The main zones of soil contaminations were to the west,

northwest and northeast of Chernobylnorthwest and northeast of Chernobyl

However, after May 1st , substantial increase of the However, after May 1st , substantial increase of the

emission was reported, with the maximum on May 5themission was reported, with the maximum on May 5th

19861986

Since April 30th, during heavy rainfall in south central Since April 30th, during heavy rainfall in south central Europe, a radioactive material was transported into Europe, a radioactive material was transported into Croatia - mostly to northwestern partCroatia - mostly to northwestern part

AccumulatedAccumulated I- I-131131 deposition in KBq/mdeposition in KBq/m²²,, as calculated as calculated

by the MESUS model, for the period April 26th - May 6thby the MESUS model, for the period April 26th - May 6th 1986, for European countries (excluding former USSR):1986, for European countries (excluding former USSR):

Poland 110Poland 110 Austria 20 - 150Austria 20 - 150 Italy 5 - 100Italy 5 - 100 Bavaria 130Bavaria 130 ex Czechoslovakia 50ex Czechoslovakia 50 Croatia 100Croatia 100 W. Europe 0 - 20W. Europe 0 - 20

Estimated accumulation in thyroid ofEstimated accumulation in thyroid of

children and adolescents was 0,05 – 200 mSv,children and adolescents was 0,05 – 200 mSv, meaning up to 20 cGymeaning up to 20 cGy

The risk of cancer increases progressivelyThe risk of cancer increases progressively

from 10 cGy up to 1500 cGy; larger doses arefrom 10 cGy up to 1500 cGy; larger doses are cellulicidal, so the risk of getting cancer iscellulicidal, so the risk of getting cancer is lowerlower

After latent period, of about 3 years after exposal, After latent period, of about 3 years after exposal,

the first childhood “Chernobyl” papillary cancersthe first childhood “Chernobyl” papillary cancers

of thyroid glandof thyroid gland (ChPTCs) appeared(ChPTCs) appeared

CHARACTERISTICS OF ChPTCCHARACTERISTICS OF ChPTC

Frequently associated with autoimmune thyroiditisFrequently associated with autoimmune thyroiditis Solid/follicular subtype of ChPTCSolid/follicular subtype of ChPTC Extrathyroid spreadingExtrathyroid spreading Common regional and distant metastasesCommon regional and distant metastases Rearrangement of the RET oncogene - RET PTC 1Rearrangement of the RET oncogene - RET PTC 1

(lower doses), RET PTC 3 (higher doses)(lower doses), RET PTC 3 (higher doses)

The rationale of our research is to evaluateThe rationale of our research is to evaluate

the Chernobyl catastrophe as a causativethe Chernobyl catastrophe as a causative

factor of accelerated increase of the thyroidfactor of accelerated increase of the thyroid

cancer and to anticipate the possible furthercancer and to anticipate the possible further

increase of incidence in the next yearsincrease of incidence in the next years

In Ukraine and Belarus, in 50 years followingIn Ukraine and Belarus, in 50 years following

the Chernobyl catastrophe, up to 50.000 the Chernobyl catastrophe, up to 50.000

people are expected to develop thyroid cancerpeople are expected to develop thyroid cancer

The incidence rate for children’s PTC in The incidence rate for children’s PTC in Chernobyl Chernobyl

area raised of factor 100 – from 0,1 to 10area raised of factor 100 – from 0,1 to 10

Our research is aimed in threeOur research is aimed in three directions: directions:

Comparison of the PTC prior and after latent period Comparison of the PTC prior and after latent period of Chernobyl, regarding autoimmune thyroiditis, of Chernobyl, regarding autoimmune thyroiditis, adenomas and nodules coinciding tumorsadenomas and nodules coinciding tumors

Epidemiological tracing target cohorts of patients Epidemiological tracing target cohorts of patients born 1966 – 1986born 1966 – 1986

Attempt to find rearrangements of thyrosine-kinase Attempt to find rearrangements of thyrosine-kinase domains of the RET genes, in group of 50 patients domains of the RET genes, in group of 50 patients with PTCwith PTC

A) HistologyA) Histology

We compared 3 groups of patients We compared 3 groups of patients operated during following periods:operated during following periods:

II 1985 – 1987 100 PTC 1985 – 1987 100 PTC

(prechernobyl and(prechernobyl and

latent period)latent period)

II II 1995 – 2000 202 PTC 1995 – 2000 202 PTC

(early postchernobyl(early postchernobyl

manifest period)manifest period) III III 2001 – 2004 233 PTC 2001 – 2004 233 PTC

(later postchernobyl(later postchernobyl

manifest period)manifest period)

All slides were rewieved by the group ofAll slides were rewieved by the group of

our pathologistsour pathologists

The results are presented in the followingThe results are presented in the following

table:table:

Papillary thyroid cancer inside adenoma

Lymphocytic thyroiditisaround papillary thyroid

cancer

COMPARISON OF PTC ACCORDING TO HISTOLOGICAL COMPARISON OF PTC ACCORDING TO HISTOLOGICAL FINDINGS IN THE REMAINING PARENCHYMAFINDINGS IN THE REMAINING PARENCHYMA

SURGERYSURGERY

REMAINING PERIOD REMAINING PERIOD

PARENPARENCHYMACHYMA

1985 - 1987 1995 - 2000 2001 - 2004

N % N % N %

NORMAL 85 85,0 98 48,5 99 42,5

AUTOIMMUNE THYROIDITIS 11 11,0 64 31,7 82 35,2

ADENOMAS 3 3,0 24 11,9 19 8,2

BENIGN NODULES / / 8 3,9 25 10,7

AUTOIMMUNE THYROIDITIS AND ADENOMAS / / / / 3 1,3

ADENOMAS AND NODULES / / / / 1 0,4

TOXIC GOITERS 1 1,0 8 4,0 4 1,7

TOTAL 100 100,0 202 100,0 233 100,0

In group of non-affected by radioiodine (In group of non-affected by radioiodine (II) ) 85%85% of of parenchyma around tumor was normal, opposite toparenchyma around tumor was normal, opposite to only only 48,5%48,5% in earlier radioiodine affected group ( in earlier radioiodine affected group (IIII), ), and and 42,5%42,5% in the latter group ( in the latter group (IIIIII))

The differences between groupThe differences between group I I vs vs II II + + IIIIII are are statistically significantstatistically significant (p(p<<0,01)0,01) In group In group II autoimmune thyroiditis was found in autoimmune thyroiditis was found in

only only 11%11% of thyroids, comparing with of thyroids, comparing with 31,7% 31,7% andand

35,2%35,2%, in groups , in groups IIII and and IIIIII respectively respectively In group In group I I benign adenomas were found in onlybenign adenomas were found in only

3%3%,, comparing with comparing with 11,9%11,9% and and 8,2%8,2%, in groups, in groups II II

and and IIIIII respectively respectively Both differences are Both differences are statistically significantstatistically significant

NoneNone of thyroids in group of thyroids in group II was accompanied by was accompanied by

autoimmune thyroiditis and/or adenomas and/orautoimmune thyroiditis and/or adenomas and/or

adenomas + nodules, as it was the case in group adenomas + nodules, as it was the case in group IIIIII

Conclusions:Conclusions:

These data suggest that Chernobyl catastrophe could These data suggest that Chernobyl catastrophe could be one of the causes of increasing incidence of PTC in be one of the causes of increasing incidence of PTC in CroatiaCroatia

B) EpidemiologyB) Epidemiology

In epidemiological part of our study we In epidemiological part of our study we

compared:compared: 1. Incidence rate of thyroid cancer vs all tumor sites 1. Incidence rate of thyroid cancer vs all tumor sites

since 1968 to 2002since 1968 to 2002 2. Incidence rate in cohorts born 1966 - 1986 vs all2. Incidence rate in cohorts born 1966 - 1986 vs all

the othersthe others 3. Prevalence of thyroid cancer according 3. Prevalence of thyroid cancer according

accumulated deposition of accumulated deposition of I-I-131131 (in KBq/m (in KBq/m²²) in all ) in all

the counties of Croatiathe counties of Croatia

Incidence rate of malignant tumors in Croatia Incidence rate of malignant tumors in Croatia 1968 – 2002 (all sites)1968 – 2002 (all sites)

incidencije svih ca

0.00

100.00

200.00

300.00

400.00

500.00

600.00

godine

inci

den

cija incidencija uk

incidencija m

incidencija ž

The incidence rate for all sites has beenThe incidence rate for all sites has been doubled since 1968 to 2002 includingdoubled since 1968 to 2002 including

Incidence rate

TOTALMALES FEMALES

YEARS

INCIDENCE

Incidence rate of thyroid cancer in CroatiaIncidence rate of thyroid cancer in Croatia(1968 – 2002)(1968 – 2002)

incidencije ca štitnjače

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

godine

inci

den

cija

incidencija uk

incidencija m

incidencija ž

The incidence rate of TC since 1968 to 2002 raised for The incidence rate of TC since 1968 to 2002 raised for females 4,3 times , for males 4 times and in total 4,4 timesfemales 4,3 times , for males 4 times and in total 4,4 times

F:11,8

T:7,5

M:2,8F:2,7

T:1,7

M:0,7

TOTALMALES FEMALES

YEARS

INCIDENCE

incidencije ca štitnjače

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.0068 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98

2000

godine

inci

den

cija

incidencija uk

incidencija m

incidencija ž

0

2

4

6

8

10

12

14

1975 1978 1981 1984 1987 1990 1993 1996 1999

Year of diagnosis

Rate

per

100

,000

pop

ulat

ion

males females persons

F 1,7xF 1,7xT 1,5xT 1,5xM 1,5xM 1,5x

F 1,8F 1,8T 1,4T 1,4M 0,8M 0,8

F 3,1F 3,1T 2,2T 2,2M 1,2M 1,2

F 11,8F 11,8

T 7,5T 7,5

M 2,8M 2,8

F 3,3F 3,3T 1,9T 1,9M 0,5M 0,5

Croatia

England

COMPARISON CANCER REGISTRY DATA BETWEEN CROATIA AND ENGLAND

In the period 1975 - 2002 the In the period 1975 - 2002 the incidence rate in Croatia raised incidence rate in Croatia raised 3,9 times, and in England only3,9 times, and in England only1,5 times1,5 times

Moreover, English curve showsMoreover, English curve showsonly slight raising of incidenceonly slight raising of incidencerate, while Croatian curve showsrate, while Croatian curve showsunexpectedly accelerated raisingunexpectedly accelerated raisingof incidence rate in mid 1990s. of incidence rate in mid 1990s.

F 3,5xF 3,5xT 3,9xT 3,9xM 5,6xM 5,6x

udio ca štitnjače u svim ca

0

0.5

1

1.5

2

2.5

3

3.5

godine

ud

io (

%) udio uk

udio m

udio ž

Total 1968 = 0,8% Total 1968 = 0,8% 2002 = 1,7% 2002 = 1,7% Males 1968 = 0,3% Males 1968 = 0,3% 2002 = 0,6% 2002 = 0,6% Females 1968 = 1,3% Females 1968 = 1,3% 2002 = 3,1% 2002 = 3,1%

INCREASING PREVALENCE OF THYROID CANCER AMONG INCREASING PREVALENCE OF THYROID CANCER AMONG ALL TUMOR SITES IN CROATIA ALL TUMOR SITES IN CROATIA

TOTALMALES FEMALES

YEARS

%

INCIDENCE RATE OF THYROID CANCERINCIDENCE RATE OF THYROID CANCERCOHORTS OF BORN 1966 - 1986 COHORTS OF BORN 1966 - 1986

BEFORE AND AFTER CHERNOBYLBEFORE AND AFTER CHERNOBYL

1966 1986 1993 2002

latency manifestation

5 years 35 years

incidencije u

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 9820

00

godine

inci

de

nci

ja u 5-35

u >35

5 per. Mov. Avg. (u 5-35)

5 per. Mov. Avg. (u >35)

COMPARISON OF INCREASING INCIDENCE RATEOF THYROID CANCER - COHORTS 5 - 35 vs >35 yrs TOTAL

1970 2002 >35 ~2x 5 – 35 ~6x

YEARS

INCIDENCE

<35

>35

incidencije ž

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

godine

inci

de

nci

ja

ž 5-35

ž >35

5 per. Mov. Avg. (ž >35)

5 per. Mov. Avg. (ž 5-35)

1970 2002 >35 ~2x 5 - 35 ~9x

Porast incidencije 5-35 i >35, ženeCOMPARISON OF INCREASING INCIDENCE RATEOF THYROID CANCER - COHORTS 5 - 35 vs >35 yrs FEMALES

YEARS

INCIDENCE

<35

>35

incidencije m

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

godine

inci

de

nci

ja m 5-35

m >35

5 per. Mov. Avg. (m >35)

5 per. Mov. Avg. (m 5-35)

Porast incidencije 5-35 i >35, muškarci

1970 2002 >35 ~2x 5 - 35 ~6x

COMPARISON OF INCREASING INCIDENCE RATEOF THYROID CANCER - COHORTS 5 - 35 vs >35 yrs MALES

YEARS

INCIDENCE

<35

>35

udio ca u riz.sk. u ukupnom broju ca

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

40.00

godine

%

udio uk

udio ž

trend ž

trend u

25%

15%

INCREASING PREVALENCE OF COHORTS INCREASING PREVALENCE OF COHORTS <<35 yrs vs ALL THE OTHERS35 yrs vs ALL THE OTHERS

YEARS

FEMALESTOTAL

%

Increased incidence of thyroid cancer in Croatia in Increased incidence of thyroid cancer in Croatia in

late 1990slate 1990s Increased prevalence of thyroid cancer in Croatia Increased prevalence of thyroid cancer in Croatia

among all the other tumor sitesamong all the other tumor sites Increased incidence/prevalence in Croatia in Increased incidence/prevalence in Croatia in

cohorts born 1966 -1986 vs elderscohorts born 1966 -1986 vs elders

Conclusions:

According to meteorologic situation over Croatia,According to meteorologic situation over Croatia,

the highest deposition of radioiodine was in thethe highest deposition of radioiodine was in the

period since April 29th to May 4th 1986period since April 29th to May 4th 1986

Therefore, we elaborated detailed maps ofTherefore, we elaborated detailed maps of

radioiodine distribution, in all the counties of radioiodine distribution, in all the counties of

Croatia,Croatia, in that period

Total wet deposition (Bq/mTotal wet deposition (Bq/m²²) ) April 29th – May 4th, 1986April 29th – May 4th, 1986

PROJEKT: Uzrok porasta incidencije raka štitne žlijezde u Republici Hrvatskoj (#0129011)

TABLICA 6. USPOREDBA NOVOOBOLJELIH: SVI TUMORI I TUMORI ŠTITNE ŽLIJEZDE PO ŽUPANIJAMA, OVISNO O IDENTIČNIM DOBNIM SKUPINAMAU RAZDOBLJU 1988 - 1995 i 1996 - 2002

A - skupine rođene 1966 - 1986B - skupine rođene <1966 i >1986

A B % A A B % A A B % A A B % A

Bjelovarsko-Bilogorska 102 3.952 2,52% 123 3.762 3,17% 1 36 2,70% 6 36 14,29%

Brodsko-Posavska 131 4.545 2,80% 132 4.815 2,67% 6 29 17,14% 6 29 17,14%

Dubrovačko-Neretvanska 90 2.981 2,93% 107 3.384 3,07% 1 28 3,45% 9 52 14,75%

Grad Zagreb 639 21.840 2,84% 772 24.777 3,02% 47 292 13,86% 70 480 12,73%

Istarska 159 5.651 2,74% 193 6.156 3,04% 9 27 25,00% 10 53 15,87%

Karlovačka 138 4.683 2,86% 82 4.844 1,66% 9 35 20,45% 7 46 13,21%

Koprivničko-Križevačka 123 3.833 3,11% 121 3.584 3,27% 6 43 12,24% 8 33 19,51%

Krapinsko-Zagorska 111 4.176 2,59% 112 4.081 2,67% 1 34 2,86% 9 37 19,57%

Ličko-Senjska 32 1.610 1,95% 34 1.580 2,11% 0 11 0,00% 2 12 14,29%

Međimurska 93 2.936 3,07% 126 2.983 4,05% 1 32 3,03% 9 37 19,57%

Osječko-Baranjska 227 7.887 2,80% 291 8.756 3,22% 15 68 18,07% 22 97 18,49%

Požeško-Slavonska 71 2.165 3,18% 60 2.239 2,61% 5 14 26,32% 7 16 30,43%

Primorsko-Goranska 282 9.105 3,00% 212 9.092 2,28% 12 65 15,58% 8 67 10,67%

Sisačko-Moslavačka 141 5.299 2,59% 134 5.657 2,31% 7 54 11,48% 12 66 15,38%

Splitsko-Dalmatinska 303 9.571 3,07% 441 11.985 3,55% 11 123 8,21% 40 281 12,46%

Šibensko-Kninska 69 2.641 2,55% 91 3.111 2,84% 2 20 9,09% 3 23 11,54%

Varaždinska 132 4.585 2,80% 159 5.536 2,79% 8 44 15,38% 27 92 22,69%

Virovitičko-Podravska 70 2.316 2,93% 69 2.563 2,62% 1 21 4,55% 2 30 6,25%

Vukovarsko-Srijemska 122 3.769 3,14% 107 4.486 2,33% 8 24 25,00% 8 58 12,12%

Zadarska 125 3.626 3,33% 155 4.151 3,60% 6 36 14,29% 4 44 8,33%

Zagrebačka 207 7.127 2,82% 253 7.757 3,16% 11 85 11,46% 23 99 18,85%

RH Nepoznato 87 1.285 6,34% 247 1.959 11,20% 1 26 3,70% 2 27 6,90%

Ukupno 3.454 115.583 2,90% 4.021 127.258 3,06% 168 1.147 12,78% 294 1.715 14,63%

povećanje: 16,42% 10,10% povećanje: 75,00% 49,52%

incidencija tumora štitne žlijezde >7%

incidencija tumora štitne žlijezde >0% i <7%

incidencija bez promjene

negativna incidencija

Svi tumori ŠtitnjačaPeriod 88-95 Period 96-02 Period 88-95 Period 96-02

COMPARISON OF NEW CASES: TUMORS ALL SITES vs THYROID CANCERS IN THE COUNTIES ACCORDING TO COHORTS BORN 1966 -1986 (A) AND COHORTS BORN <1966 AND >1986 (B)

COUNTY ALL SITES THYROID

increase increase

increase of thyroid tumors >7% <7%no increasedecrease

total

Increasing incidence rate of all sitesperiod ’88-’95 vs period ’96-’02cohorts 1966-86

COUNTIES

significant increase

slight increase

no increase

decrease

Without significant increase in both observed periodsWithout significant increase in both observed periods

Increasing incidence rate of thyroid cancer period ’88-’95 vs period ’96-’02 cohorts 1966-86

significant increase

slight increase

no increase

decrease

COUNTIES

In northern and western counties slight to In northern and western counties slight to significant increasesignificant increase

These data suggest positive correlation between These data suggest positive correlation between

the accumulated deposition of radioiodine and thethe accumulated deposition of radioiodine and the

incidence rate of thyroid cancerincidence rate of thyroid cancer There is no correlation between the accumulated There is no correlation between the accumulated

deposition of radioiodine and the incidence rate deposition of radioiodine and the incidence rate

of all the other tumor sitesof all the other tumor sites

Geiger - Müller counter

Conclusions:

C) Molecular biological analysisC) Molecular biological analysis

Molecular biological analyzes are Molecular biological analyzes are “in tractu”“in tractu”, so no, so no

conclusions, considering genetic alterations, can beconclusions, considering genetic alterations, can be

referred todayreferred today

As far as European population is concerned, theAs far as European population is concerned, the

first results for 22 European countries arefirst results for 22 European countries are

underestimated of factor 4, for the incidence of underestimated of factor 4, for the incidence of

fatal and non-fatal thyroid cancer, caused by fatal and non-fatal thyroid cancer, caused by

Chernobyl catastropheChernobyl catastrophe““Thyroid dosimetry in Europe following the Chernobyl Thyroid dosimetry in Europe following the Chernobyl accident “ accident “ Brit. Journal of Rad. 73 (870): 636-40, 2000 JunBrit. Journal of Rad. 73 (870): 636-40, 2000 Jun

The same results were referred from:The same results were referred from:• DebrecenDebrecen (Lukacs et al),(Lukacs et al), 19971997• Western PolandWestern Poland (Niedziela et al),(Niedziela et al), 20032003• Cancer Registry of Czech RepublicCancer Registry of Czech Republic (Murbeth et al), 2004(Murbeth et al), 2004

CONCLUSIONS:CONCLUSIONS:

Histological and epidemiological data, together Histological and epidemiological data, together with clinical observations and data from mid-with clinical observations and data from mid-eastern European countries, suggest that eastern European countries, suggest that increase of thyroid cancer, particularly in increase of thyroid cancer, particularly in population born 1966 - 1986, is caused, at least population born 1966 - 1986, is caused, at least partly, by Chernobyl catastrophepartly, by Chernobyl catastrophe

Have a nice time in Zagreb!