3rd International Course Multidisciplinary Approach on Thyroid Gland and Oral Cavity Carcinoma Zagreb – Croatia, September, 1st - 3rd, 2005 THE INCREASING INCIDENCE OF THYROID CANCER IN CROATIA COINCIDING WITH CHERNOBYL NUCLEAR CATASTROPHE Radetić, M., Kovačić, M., Parazajder, D., Radetić, Ma., Špoler Čanić, K.* OTOLARYNGOLOGY & HEAD AND NECK SURGERY DEPARTMENT, OTOLARYNGOLOGY & HEAD AND NECK SURGERY DEPARTMENT, GENERAL HOSPITAL “SVETI DUH”, ZAGREB, CROATIA GENERAL HOSPITAL “SVETI DUH”, ZAGREB, CROATIA *THE STATE HYDROMETEOROLOGICAL INSTITUTE OF REPUBLIC OF *THE STATE HYDROMETEOROLOGICAL INSTITUTE OF REPUBLIC OF CROATIA, ZAGREB, CROATIA CROATIA, ZAGREB, CROATIA

During the accident at Chernobyl nuclear power plant, on April 26th 1986, about 100 MCi of short- lived radioiodines During the accident at Chernobyl nuclear power plant, on April 26th 1986, about 100 MCi of short- lived radioiodines (I- 132, 133, 135 ) and 40 MCi (I- 132, 133, 135 ) and 40 MCi of I- 131 were released into the atmosphere of I- 131 were released into the 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 Chernobyl northwest 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 5th emission was reported, with the maximum on May 5th

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

Accumulated I- 131 deposition in KBq/m², as calculated Accumulated I- 131 deposition in KBq/m², as calculated by the MESUS model, for the period April 26th - May 6th by 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 110 Poland 110 Austria Austria Italy Italy Bavaria 130 Bavaria 130 ex Czechoslovakia 50 ex Czechoslovakia 50 Croatia 100 Croatia 100 W. Europe W. Europe

Estimated accumulation in thyroid of Estimated accumulation in thyroid of children and adolescents was 0,05 – 200 mSv, children and adolescents was 0,05 – 200 mSv, meaning up to 20 cGy meaning up to 20 cGy The risk of cancer increases progressively The risk of cancer increases progressively from 10 cGy up to 1500 cGy; larger doses are from 10 cGy up to 1500 cGy; larger doses are cellulicidal, so the risk of getting cancer is cellulicidal, so the risk of getting cancer is lower lower

After latent period, of about 3 years after exposal, After latent period, of about 3 years after exposal, the first childhood “Chernobyl” papillary cancers the first childhood “Chernobyl” papillary cancers of thyroid gland (ChPTCs) appeared of thyroid gland (ChPTCs) appeared

CHARACTERISTICS OF ChPTC Frequently associated with autoimmune thyroiditis Frequently associated with autoimmune thyroiditis Solid/follicular subtype of ChPTC Solid/follicular subtype of ChPTC Extrathyroid spreading Extrathyroid spreading Common regional and distant metastases Common regional and distant metastases Rearrangement of the RET oncogene - RET PTC 1 (lower doses), RET PTC 3 (higher doses) Rearrangement of the RET oncogene - RET PTC 1 (lower doses), RET PTC 3 (higher doses)

The rationale of our research is to evaluate The rationale of our research is to evaluate the Chernobyl catastrophe as a causative the Chernobyl catastrophe as a causative factor of accelerated increase of the thyroid factor of accelerated increase of the thyroid cancer and to anticipate the possible further cancer and to anticipate the possible further increase of incidence in the next years increase of incidence in the next years

In Ukraine and Belarus, in 50 years following In Ukraine and Belarus, in 50 years following the Chernobyl catastrophe, up to the Chernobyl catastrophe, up to people are expected to develop thyroid cancer people are expected to develop thyroid cancer The incidence rate for children’s PTC in Chernobyl The incidence rate for children’s PTC in Chernobyl area raised of factor 100 – from 0,1 to 10 area raised of factor 100 – from 0,1 to 10

Our research is aimed in three directions: Our research is aimed in three directions: Comparison of the PTC prior and after latent period of Chernobyl, regarding autoimmune thyroiditis, adenomas and nodules coinciding tumors Comparison of the PTC prior and after latent period of Chernobyl, regarding autoimmune thyroiditis, adenomas and nodules coinciding tumors Epidemiological tracing target cohorts of patients born 1966 – 1986 Epidemiological tracing target cohorts of patients born 1966 – 1986 Attempt to find rearrangements of thyrosine-kinase domains of the RET genes, in group of 50 patients with PTC Attempt to find rearrangements of thyrosine-kinase domains of the RET genes, in group of 50 patients with PTC

A) Histology We compared 3 groups of patients operated during following periods: A) Histology We compared 3 groups of patients operated during following periods: I 1985 – PTC I 1985 – PTC (prechernobyl and (prechernobyl and latent period) latent period) II 1995 – PTC II 1995 – PTC (early postchernobyl (early postchernobyl manifest period) manifest period) III 2001 – PTC III 2001 – PTC (later postchernobyl (later postchernobyl manifest period) manifest period)

All slides were rewieved by the group of All slides were rewieved by the group of our pathologists our pathologists The results are presented in the following The results are presented in the following table: table: Papillary thyroid cancer inside adenoma Lymphocytic thyroiditis around papillary thyroid cancer

COMPARISON OF PTC ACCORDING TO HISTOLOGICAL FINDINGS IN THE REMAINING PARENCHYMA COMPARISON OF PTC ACCORDING TO HISTOLOGICAL FINDINGS IN THE REMAINING PARENCHYMA SURGERY SURGERY REMAINING PERIOD REMAINING PERIOD PAREN CHYMA PAREN CHYMA N%N%N% NORMAL8585,09848, ,5 AUTOIMMUNE THYROIDITIS11 11,06431, ,235,2 ADENOM AS 33,02411,919 8, 2 BENIGN NODUL ES // 8 3,92510,7 AUTOIMMUNE THYROIDITIS AND ADENOMAS //// 3 1, 3 ADENOM AS AND NODUL ES //// 1 0,4 TOXIC GOITERS 11,0 8 4,0 4 1,7 TOTAL , , ,0

In group of non-affected by radioiodine ( I ) 85% of In group of non-affected by radioiodine ( I ) 85% of parenchyma around tumor was normal, opposite to parenchyma around tumor was normal, opposite to only 48,5% in earlier radioiodine affected group ( II ), only 48,5% in earlier radioiodine affected group ( II ), and 42,5% in the latter group ( III ) and 42,5% in the latter group ( III ) The differences between group I vs II + III are The differences between group I vs II + III are statistically significant (p<0,01) statistically significant (p<0,01) In group I autoimmune thyroiditis was found in In group I autoimmune thyroiditis was found in only 11% of thyroids, comparing with 31,7% and only 11% of thyroids, comparing with 31,7% and 35,2%, in groups II and III respectively 35,2%, in groups II and III respectively In group I benign adenomas were found in only In group I benign adenomas were found in only 3%, comparing with 11,9% and 8,2%, in groups II 3%, comparing with 11,9% and 8,2%, in groups II and III respectively and III respectively Both differences are statistically significant Both differences are statistically significant

None of thyroids in group I was accompanied by None of thyroids in group I was accompanied by autoimmune thyroiditis and/or adenomas and/or autoimmune thyroiditis and/or adenomas and/or adenomas + nodules, as it was the case in group III adenomas + nodules, as it was the case in group III Conclusions: These data suggest that Chernobyl catastrophe could be one of the causes of increasing incidence of PTC in Croatia

B) 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 2002 since 1968 to Incidence rate in cohorts born vs all 2. Incidence rate in cohorts born vs all the others the others 3. Prevalence of thyroid cancer according 3. Prevalence of thyroid cancer according accumulated deposition of I- 131 (in KBq/m²) in all accumulated deposition of I- 131 (in KBq/m²) in all the counties of Croatia the counties of Croatia

Incidence rate of malignant tumors in Croatia 1968 – 2002 (all sites) The incidence rate for all sites has been doubled since 1968 to 2002 including doubled since 1968 to 2002 including Incidence rate TOTAL MALES FEMALES YEARS INCIDENCEINCIDENCE

Incidence rate of thyroid cancer in Croatia (1968 – 2002) The incidence rate of TC since 1968 to 2002 raised for females 4,3 times, for males 4 times and in total 4,4 times F:11,8 T:7,5 M:2,8 F:2,7 T:1,7 M:0,7 TOTAL MALES FEMALES YEARS INCIDENCEINCIDENCE

F 1,7x T 1,5x M 1,5x F 1,8 T 1,4 M 0,8 F 3,1 T 2,2 M 1,2 F 11,8 T 7,5 M 2,8 F 3,3 T 1,9 M 0,5 Croatia England COMPARISON CANCER REGISTRY DATA BETWEEN CROATIA AND ENGLAND In the period the incidence rate in Croatia raised 3,9 times, and in England only 1,5 times Moreover, English curve shows only slight raising of incidence rate, while Croatian curve shows unexpectedly accelerated raising of incidence rate in mid 1990s. F 3,5x T 3,9x M 5,6x

Total 1968 = 0,8%  2002 = 1,7% Total 1968 = 0,8%  2002 = 1,7% Males 1968 = 0,3%  2002 = 0,6% Males 1968 = 0,3%  2002 = 0,6% Females 1968 = 1,3%  2002 = 3,1% Females 1968 = 1,3%  2002 = 3,1% INCREASING PREVALENCE OF THYROID CANCER AMONG ALL TUMOR SITES IN CROATIA TOTAL MALES FEMALES YEARS %

INCIDENCE RATE OF THYROID CANCER COHORTS OF BORN BEFORE AND AFTER CHERNOBYL latency manifestation 5 years 35 years

COMPARISON OF INCREASING INCIDENCE RATE OF THYROID CANCER - COHORTS vs >35 yrs TOTAL 1970  2002 >35 ~2x 5 – 35 ~6x YEARS INCIDENCEINCIDENCE <35 >35

1970  2002 >35 ~2x ~9x Porast incidencije 5-35 i >35, žene COMPARISON OF INCREASING INCIDENCE RATE OF THYROID CANCER - COHORTS vs >35 yrs FEMALES YEARS INCIDENCEINCIDENCE <35 >35

Porast incidencije 5-35 i >35, muškarci 1970  2002 >35 ~2x ~6x COMPARISON OF INCREASING INCIDENCE RATE OF THYROID CANCER - COHORTS vs >35 yrs MALES YEARS INCIDENCEINCIDENCE <35 >35

25% 15% INCREASING PREVALENCE OF COHORTS <35 yrs vs ALL THE OTHERS YEARS FEMALES TOTAL %

Increased incidence of thyroid cancer in Croatia in Increased incidence of thyroid cancer in Croatia in late 1990s late 1990s Increased prevalence of thyroid cancer in Croatia Increased prevalence of thyroid cancer in Croatia among all the other tumor sites among all the other tumor sites Increased incidence/prevalence in Croatia in Increased incidence/prevalence in Croatia in cohorts born vs elders cohorts born vs elders Conclusions:

According to meteorologic situation over Croatia, According to meteorologic situation over Croatia, the highest deposition of radioiodine was in the the highest deposition of radioiodine was in the period since April 29th to May 4th 1986 period since April 29th to May 4th 1986 Therefore, we elaborated detailed maps of Therefore, 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/m²) April 29th – May 4th, 1986

COMPARISON OF NEW CASES: TUMORS ALL SITES vs THYROID CANCERS IN THE COUNTIES ACCORDING TO COHORTS BORN (A) AND COHORTS BORN 1986 (B) COUNTY ALL SITES THYROID increase increase of thyroid tumors >7% <7% no increase decrease total

Increasing incidence rate of all sites period ’88-’95 vs period ’96-’02 cohorts COUNTIES significant increase slight increase no increase decrease Without significant increase in both observed periods

Increasing incidence rate of thyroid cancer period ’88-’95 vs period ’96-’02 cohorts significant increase slight increase no increase decrease COUNTIES In northern and western counties slight to significant increase

These data suggest positive correlation between These data suggest positive correlation between the accumulated deposition of radioiodine and the the accumulated deposition of radioiodine and the incidence rate of thyroid cancer incidence 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 sites of all the other tumor sites Geiger - Müller counter Conclusions:

C) Molecular biological analysis Molecular biological analyzes are “in tractu”, so no Molecular biological analyzes are “in tractu”, so no conclusions, considering genetic alterations, can be conclusions, considering genetic alterations, can be referred today referred today

As far as European population is concerned, the As far as European population is concerned, the first results for 22 European countries are first 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 catastrophe Chernobyl catastrophe “Thyroid dosimetry in Europe following the Chernobyl accident “ Brit. Journal of Rad. 73 (870): , 2000 Jun accident “ Brit. Journal of Rad. 73 (870): , 2000 Jun  The same results were referred from: Debrecen (Lukacs et al), 1997 Debrecen (Lukacs et al), 1997 Western Poland (Niedziela et al), 2003 Western Poland (Niedziela et al), 2003 Cancer Registry of Czech Republic (Murbeth et al), 2004 Cancer Registry of Czech Republic (Murbeth et al), 2004

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

Have a nice time in Zagreb!