Radiol Oncol 2020; 54(2): 187-193. doi: 10.2478/raon-2020-0023
187
research article
Dietary iodine intake, therapy with 
radioiodine, and anaplastic thyroid carcinoma
Nikola Besic1,Barbara Gazic2
1 Department of Surgical Oncology, Institute of Oncology Ljubljana, Slovenia 
2 Department of Pathology, Institute of Oncology Ljubljana, Slovenia
Radiol Oncol 2020; 54(2): 187-193.
Received 16 November 2019
Accepted 30 March 2020
Correspondence to: Prof. Nikola Bešić, M.D., Ph.D., Department of Surgical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 
1000 Ljubljana, Slovenia. E-mail: nbesic@onko-i.si
Disclosure: No potential conflicts of interest were disclosed. 
Background. Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. The aim of the study was to de-
termine the correlation between a higher dietary intake of iodine, frequency of ATC and the characteristics of ATC, 
and to find out how often patients with ATC had a history of radioiodine (RAI) therapy. 
Patients and methods. This retrospective study included 220 patients (152 females, 68 males; mean age 68 years) 
with ATC who were treated in our country from 1972 to 2017. The salt was iodinated with 10 mg of potassium iodide/
kg before 1999, and with 25 mg of potassium iodide/kg thereafter. The patients were assorted into 15-year periods: 
1972–1986, 1987–2001, and 2002–2017. 
Results. The incidence of ATC decreased after a higher iodination of salt (p = 0.04). Patients are nowadays older (p = 
0.013) and have less frequent lymph node metastases (p = 0.012). The frequency of distant metastases did not change 
over time. The median survival of patients in the first, second, and third periods was 3, 4, and 3 months, respectively (p 
< 0.05). The history of RAI therapy was present in 7.7% of patients. 
Conclusions. The number of patients with a history of RAI therapy did not change statistically over time. The inci-
dence of ATC in Slovenia decreased probably because of higher salt iodination.
Key words: anaplastic thyroid carcinoma; iodination of salt; treatment, survival
Introduction
Anaplastic thyroid cancer (ATC) is one of the most 
aggressive tumors known in humans.1 It is a locally 
widely invasive disease which progresses despite 
treatment and finally results in metastatic disease 
in the majority of patients.2 Fortunately, ATC is a 
rare disease and the estimated annual incidence is 
about two per million of the population.3,4 In the 
USA and Japan, ATC represents less than 2% of 
thyroid carcinomas.5,6 On the other hand, the inci-
dence of ATC has been stable in the last decades.1,7
In the literature, there are only limited data 
about the history of radioiodine (RAI) therapy in 
patients with ATC. The aim of the study was to 
find out how often patients had a history of RAI 
therapy. In one of our recent studies we compared 
the incidence of ATC during the periods when the 
intake of potassium iodide in salt was 10 and 25 
mg/kg in the Republic of Slovenia.8 It was observed 
that the incidence of ATC decreased with a higher 
iodination of salt in Slovenia.8 Another aim of the 
study was to determine the correlation between a 
higher dietary intake of iodine, frequency of ATC 
and the characteristics of ATC. 
Patients and methods
The data on the patients with ATC treated at the 
Institute of Oncology in Ljubljana in the years 
1972–2017 were collected retrospectively. During 
this period, there were 220 patients (152 females, 
68 males; median age 69 years; mean age 68 years) 
with ATC. The Cancer Registry of Republic of 
Slovenia is one of the oldest population-based 
Radiol Oncol 2020; 54(2): 187-193.
Besic N and Gazic B / Dietary iodine intake and anaplastic carcinoma188
cancer registries in Europe.9 It was founded in 
1950 at the Institute of Oncology in Ljubljana as a 
special service for collecting and processing data 
on cancer incidence and cancer patients’ survival. 
Notification of cancer has been compulsory in 
Slovenia since the foundation of the Registry and 
prescribed by law.9 The main sources of data are 
notifications of cancer, gathered from all hospitals 
and diagnostic centers in Slovenia.9 Furthermore, 
all the patients with thyroid cancer are treated at 
the Institute of Oncology in Ljubljana, so our data 
represent a population based study. 
For each patient, the data on sex, age, history 
of treatment with radioiodine, clinical and tumor 
characteristics, and duration of survival were col-
lected. Distant metastases were diagnosed by clini-
cal examination and additional diagnostic proce-
dures, including lung and/or bone X-ray, radionu-
clide investigations, ultrasonography, computed 
tomography, and/or nuclear magnetic resonance 
imaging. Data about the treatment of our patients 
have already been reported.10,11
The Protocol Review Board and Ethics 
Committee of the Institute of Oncology on 12th 
December 2018 (ERID-KSOPKR/43, OIRIKE 00448) 
reviewed and approved the study, which was con-
ducted in accordance with the ethical standards 
prescribed in the Declaration of Helsinki. For retro-
spective studies, informed consent is not necessary 
according to the national regulations. The need for 
consent was waived by the Institutional Review 
Board and Ethics Committee of the Institute of 
Oncology Ljubljana.
All cases were reviewed by pathologists and cy-
topathologists at our comprehensive cancer center, 
experienced in thyroid pathology. Histological 
specimens were retrieved by surgical removal of 
the thyroid tumor, surgical biopsy, or autopsy, 
whereas cytological samples were obtained by 
fine-needle aspiration biopsy of the primary tu-
mor or its metastases. The diagnosis of ATC was 
confirmed by both histology and cytology in 75 
patients, by cytology alone in 97 patients, and by 
histology alone in 48 patients.
In Slovenia, salt was iodinated with 10 mg of po-
tassium iodide/kg and 25 mg of potassium iodide/
kg during the periods 1972–1998 and 1999–2017, 
respectively.12,13 All salt that was on the market in 
Slovenia during the first and the second 15-year pe-
riods had the required content of iodine. Slovenia 
has been considered to be an area with an adequate 
iodine supply since 1999.12,13 Since 2004, when 
Slovenia became a member of the European Union, 
salt with a lower content of iodine and Himalayan 
salt with no iodine added at all have also been 
available in health food stores. Furthermore, in the 
last decade, the use of prefabricated or frozen food 
became more popular in Slovenia. Fortunately, al-
most all households in Slovenia use salt with 25 mg 
of potassium iodide/kg, which is evident from epi-
demiological studies in schoolchildren.12,14
For the purposes of the present study, patients 
were assorted into one of three 15-year periods ac-
cording to the year of diagnosis of ATC: 1972–1986, 
1987–2001, and 2002–2017. The frequency of ATC 
during these three periods and the characteristics 
of the patients during these periods were com-
pared. 
The characteristics of the patients and tumors 
and the history of RAI therapy according to 
15-year periods were statistically analyzed using 
contingency tables and analysis of variance. SPSS 
16.0 for Windows (SPSS, Chicago, IL) was also used 
in Kaplan–Meier univariate analysis for the assess-
ment of patients’ survival.  
Results 
The incidence of ATC in Slovenia has decreased. 
ATC was diagnosed in the periods 1972–1987, 
1988–2003, and 2004-2017 in 95, 87, and 38 patients, 
respectively (p = 0.04). The mean incidence of ATC 
in the periods 1972–1986, 1987–2001, and 2002–
2017 was 6.3 (range 2–12), 5.8 (range 3-10), and 2.5 
(range 1–10) patients per year, respectively. 
The characteristics of patients and their out-
comes according to 15-year periods are presented 
in Table 1. Patients with ATC are older now than 
they used to be (p = 0.013). During the periods 
1972–1986, 1987–2001, and 2002–2017, the patients’ 
mean age was 66 (SD ±11.8) years, 69 (SD ±8.4) 
years, and 72 (SD ±11.8) years. The mean tumor 
diameter in the three time periods was 9.1 cm, 9.9 
cm, and 8.5 cm respectively. The difference was not 
statistically significant (p = 0.26). However, a tumor 
diameter larger than 10 cm was more frequent in 
patients during the 1972–2001 periods than there-
after (p < 0.05). Lymph node metastases were less 
commonly diagnosed in the last period (p = 0.012). 
However, the frequency of distant metastases did 
not change over time (p = 0.65). The median sur-
vival of patients during the first, second, and third 
15-year periods was 3 months, 4 months, and 3 
months, respectively (p < 0.05).
Cumulative yearly doses of 131I applied in medi-
cine from 1994 to 2017 in Slovenia are presented in 
Figure 1. Altogether, 17/220 (7.7%) of patients had a 
Radiol Oncol 2020; 54(2): 187-193.
Besic N and Gazic B / Dietary iodine intake and anaplastic carcinoma 189
TABLE 1. Clinical characteristics of patients and 15-year periods
Clinical characteristic Subgroup
All patients
N = 220
Number 
Patients
1972–1986
N=95
Number 
Patients
1987–2001
N = 87
Number
Patients
2002-2017
N = 38
Number
p-value
Gender
Male 68 27 29 12
0.77
Female 152 68 58 26
Age
70 years or less 124 59 49 16
0.11
71 years or more 96 36 38 22
History of radioiodine therapy
No 203 89 83 31
0.023
Yes 17 6 4 7
Previous thyroid enlargement 
(> 1 year)
No or no data 110 46 49 26
0.036
Yes 110 49 38 12
General condition
Good 92 47 33 12
0.13Moderate 58 25 20 13
Poor 70 23 34 13
Tumor growth
≥ 3 months 173 70 72 31
0.29
< 3 months 47 25 15 7
Local tumor extension
Extrathyroid 199 87 78 34
0.88
Intrathyroid 21 8 9 4
Tumor size
< 5 cm 35 20 12 3
0.0435–10 cm 105 40 39 26
≥ 10 cm 80 35 36 9
Tumor volume
(width2 x length)/2
< 50 ml 16 7 5 4
0.68
50–99 ml 37 19 14 4
100–149 ml 22 6 12 4
150–199 ml 18 9 7 2
200 ml or more 127 54 49 24
Lymph nodes
metastases
No 127 45 54 28
0.012
Yes 93 50 33 10
Distant metastases
No 113 46 48 19
0.65
Yes 107 49 39 19
Presentation of anaplastic 
carcinoma
Incidental 8 4 4 0
0.50
Evident 212 91 83 38
TNM stage
IVA 17 5 9 3
0.73IVB 96 41 39 16
IVC 107 49 39 19
Thyroid surgery
Without surgery 130 48 52 30
0.029
Biopsy 23 13 10 0
Subtotal thyroidectomy 13 10 3 0
Extracapsular lobectomy with 
isthmusectomy 17 9 7 1
Total or near-total 
thyroidectomy 37 15 15 7
Residual tumor after surgery
Biopsy or no surgery 153 61 62 30
0.55
R0 32 18 10 4
R1 18 9 6 3
R2 17 7 9 1
Lymph node dissection
No 211 90 83 38
0.36
Yes 9 5 4 0
External beam irradiation
No 37 22 11 4
0.087
Yes 183 73 76 36
External beam irradiation
Without or ≤ 20 Gy 54 33 15 6
0.001> 20 Gy and 45 Gy 74 41 26 7
> 45 Gy 92 21 46 25
Chemotherapy
No 81 38 24 19
0.04
Yes 139 57 63 19
Death because of anaplastic 
carcinoma
No (alive, other causes, 
lost from follow-up) 13 3 7 13 0.32
Yes 207 92 80 25
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Besic N and Gazic B / Dietary iodine intake and anaplastic carcinoma190
TABLE 2. Clinical characteristics of the patients and the history of radioiodine therapy 
Clinical characteristic Subgroup All patientsN = 220
Without history of 
RAI therapy N = 203
With history of RAI 
therapy N = 17 p-value
Gender
Male 68 66 2
0.10
Female 152 137 15
Age
70 years or less 124 114 10
1.00
71 years or more 96 89 7
Year of diagnosis
1972–1986 95 89 6
0.0231987–2001 87 83 4
2002–2017 38 31 7
Previous thyroid
enlargement (> 1 year)
No or no data 110 108 2
0.001
Yes 110 95 15
General condition
Good 92 85 7
0.063Moderate 58 57 1
Poor 70 61 9
Tumor growth
≥ 3 months 173 157 16
0.13
< 3 months 47 16 1
Local tumor extension
Extrathyroid 199 183 16
1.00
Intrathyroid 21 20 1
Tumor size
< 5 cm 35 34 1
0.505–10 cm 105 96 9
≥ 10 cm 80 73 7
Tumor volume
(width2 x length)/2
< 50 ml 16 16 0
0.19
50–99 ml 37 36 1
100–149 ml 22 20 2
150–199 ml 18 18 0
200 ml or more 127 113 14
Lymph nodes
metastases
No 127 117 10
1.00
Yes 93 86 7
Distant metastases
No 113 105 8
0.83
Yes 107 98 9
Presentation of
anaplastic carcinoma
Incidental 8 8 0
0.51
Evident 212 195 17
TNM stage
IVA 17 16 1
0.91IVB 96 89 7
IVC 107 98 9
Thyroid surgery
Without surgery 130 117 13
0.56
Biopsy 23 22 1
Subtotal thyroidectomy 13 12 1
Extracapsular lobectomy with 
isthmusectomy 17 17 0
Total or near-total 
thyroidectomy 37 35 2
Residual tumor
after surgery
Biopsy or no surgery 153 139 14
0.32
R0 32 32 0
R1 18 17 1
R2 17 15 2
Lymph node dissection
No 211 194 17
1.00
Yes 9 9 0
External beam 
irradiation
No 37 30 7
0.005
Yes 183 173 10
Dose of radiotherapy
Without or ≤ 20 Gy 54 47 7
0.244> 20 Gy and ≤ 45 Gy 74 70 4
> 45 Gy 92 86 6
Chemotherapy
No 81 75 6
1.00
Yes 139 128 11
Death because of ATC
No (alive, other causes, 
lost from follow up) 13 12 1 1.00
Yes 207 191 16
ATC = anaplastic thyroid cancer; RAI = radioiodine
Radiol Oncol 2020; 54(2): 187-193.
Besic N and Gazic B / Dietary iodine intake and anaplastic carcinoma 191
history of radioiodine therapy from 4 months to 40 
years before the diagnosis of ATC. The number of 
patients with ATC who had a history of RAI ther-
apy did not change statistically over time, while 
the incidence of patients with ATC decreased over 
time (p = 0.023). Data about patients with regard to 
the history of RAI therapy are presented in Table 2. 
Previous enlargement of thyroid gland was more 
common in patients with a history of RAI therapy 
in comparison to those who received no RAI (p < 
0.001). There was no difference in survival of pa-
tients with and without a history of RAI therapy 
(p = 0.49).
Discussion
Salt was iodinated in Slovenia with 10 mg of po-
tassium iodide/kg and 25 mg of potassium iodide/
kg during the periods 1972–1998 and 1999–2017, 
respectively.12,13 As expected and reported in other 
countries15, ten years after the beginning of higher 
salt iodination in Slovenia, the incidence of diffuse 
goiter in adolescents and adults decreased.12-14,16 
Furthermore, from 1999 to 2009, the incidence of 
thyroid autonomy in Slovenia decreased from 
32.7/100.000 to a 27 % lower value.12 During the 
same time period, the baseline incidence of Graves’ 
disease (27.8/100.000) did not change significantly.12 
On the other hand, the incidence of Hashimoto’s 
thyroiditis (73.2/100.000 in 1999) gradually in-
creased to levels more than twice as high as be-
fore.12 During the same time period, the incidence 
of thyroid carcinoma increased from 5.1/100.000 to 
7.25/100.000,17 but the incidence of anaplastic car-
cinoma decreased after higher iodination of salt 
in Slovenia.9 A similar observation about the inci-
dence of ATC after higher salt iodination was re-
ported in other endemic goiter regions, namely the 
Tyrol region in Austria and Argentina.18,19 
In contrast to differentiated thyroid cancer, 
which often has a subtle clinical presentation and 
may be difficult to detect, ATC is correctly diag-
nosed in nearly all cases in countries with adequate 
health care because of rapid tumor growth and the 
clinical presentation.9,20 Risk factors for ATC are: 
a history of goiter or a prior co-existing differen-
tiated thyroid cancer21-23, insufficient iodine in the 
diet9,18,24,25, low level of education21, type B blood 
group21, and presence of TERT mutation in coex-
isting thyroid papillary carcinoma26. We think that 
the drop in ATC incidence in Slovenia was mainly 
caused by higher salt iodination. A lower rate of 
goiter in Slovenia, which was also due to higher io-
dination of salt, is another risk factor that contrib-
uted to a lower incidence of ATC in our country.12,13 
Other risk factors for ATC, namely the educational 
level of the population, the socioeconomic status of 
the general population, or the rate of persons with 
type B blood group, did not change over time in 
Slovenia. 
RAI treatment for benign thyroid disease is con-
sidered to be a safe procedure.27,28 A meta-analysis 
showed no increase in the overall cancer risk af-
ter RAI treatment for hyperthyroidism. However, 
there was a trend towards increased risk of thyroid, 
stomach, and kidney cancer.27,28 In 1990, Venkatesh 
et al.29 reported in a series of 121 cases with ATC 
that seven (6%) patients had received prior RAI 
treatment. Even 7.7% of patients from our present 
study also had a history of RAI therapy. A history 
of RAI therapy in patients with ATC is more fre-
quent than the proportion of persons treated with 
RAI therapy in the Slovenian population. The use 
of 131I increased in Slovenia in the 1990s and was at 
1630.9 GBq in 1999. Thereafter, the use of 131I has 
slowly been decreasing as seen in Figure 1. In 2011, 
a total of 531 diagnostic procedures with 131I or 123I 
for thyroid imaging with an accumulative effective 
dose of 2.29 manSv were done in Slovenia.30 131I and 
123I were used in 48% and 52% of diagnostic pro-
cedures, which contributed to 69% and 31% of the 
collective effective dose for diagnostic procedures, 
respectively.30 On the other hand, the therapy with 
131I was done in 512 patients with a benign disease 
and 151 patients with a carcinoma in 2014. The 
main difference between RAI therapy in benign 
thyroid disease and thyroid carcinoma is the dose 
FIGURE 1. Cumulative yearly doses of 131I applied in medicine from 1994 to 2017 in 
Slovenia.
Radiol Oncol 2020; 54(2): 187-193.
Besic N and Gazic B / Dietary iodine intake and anaplastic carcinoma192
of RAI. In benign disease and thyroid carcinoma, 
10–15 mCi (370–555 MBq)28 and 50–200 mCi (1.8–
7.4 GBq)31 of RAI is used, respectively. 
In 1982, Kapp et al.32 reported that in two patients 
with a differentiated carcinoma, ATC occurred af-
ter irradiation. In one of them, the transformation 
to ATC occurred five years after 39.6 Gy of external 
beam irradiation, while in the other patient, ATC 
was diagnosed one year after 149 mCi of RAI. A 
component of differentiated thyroid carcinoma is 
usually identified in the primary ATC on histology 
examination.22 But, the transformation of differen-
tiated thyroid cancer to ATC may be found also in 
metastatic lymph nodes.33 It was detected in two of 
five patients during initial surgery of primary tu-
mor and regional lymph node dissection, while in 
three of five cases, the interval between treatment 
of differentiated carcinoma and occurrence of ATC 
was 46, 74, and 266 months after initial surgery. 
None of them had a history of RAI therapy, while 
one patient received external beam irradiation be-
cause of recurrent papillary carcinoma before the 
occurrence of ATC.33 
In our patients, RAI therapy was applied from 4 
months to 40 years before the diagnosis of ATC. For 
some patients with a very short interval between 
RAI therapy and the diagnosis of ATC, we could 
suspect that they already had a differentiated car-
cinoma and possibly a very small ATC which was 
not detected. Namely, in patients with Graves’ 
disease without clinically evident nodes, a thyroid 
ultrasound investigation is not recommended ac-
cording to the ATA Guidelines for diagnosis and 
management of hyperthyroidism and other causes 
of thyrotoxicosis.28 Furthermore, the use of thyroid 
scintigraphy to preselect only the cold nodules for 
cytology is advocated by some authors.34 However, 
there are at least eight case reports in the literature 
about patients with a follicular variant of papillary 
thyroid carcinoma as autonomous functioning thy-
roid nodule.35 On the other hand, ATC was also re-
ported in a long-standing multinodular goiter or a 
Hürthle cell tumor following RAI therapy.36-38 
This study has some limitations. Because it is a 
retrospective analysis over a very long time peri-
od, we do not have reliable data about the reasons 
for RAI therapy in our patients. Furthermore, di-
agnostic radiological methods have changed dra-
matically over last decades. Modern precise imag-
ing investigations have an impact on the detection 
of very small regional and/or distant metastases. 
The detection of small distant metastases possi-
bly influences therapeutic decisions, which might 
explain why a lesser proportion of patients were 
treated with radical surgery during the last 15-year 
period in comparison to prior periods. 
In the literature, data on how the patients’ and 
tumors’ characteristics in ATC have changed over 
time are very limited.39 We observed that, nowa-
days, patients are older and have less frequent 
regional metastases in comparison to previous 
periods. However, the mean tumor diameter has 
not changed significantly over time, and ATC was 
inoperable because of infiltration to the surround-
ing structures at the time of diagnosis in the ma-
jority of our patients. Unfortunately, the frequency 
of distant metastases has not changed over time. 
Thus, in Slovenia, the survival of patients with 
ATC remains short. By contrast, in South Korea 
where an opportunistic screening is performed in 
the general population for thyroid carcinoma, the 
proportion of cases with a differentiated thyroid 
carcinoma and only anaplastic foci has increased 
over time, while that of evident ATC has decreased 
from 1985 to 2013.39 As a consequence, the sur-
vival rate is significantly higher than it used to be. 
Obviously, in patients with a very early ATC, lym-
phatic invasion was the most significant postopera-
tive prognosticator, so the choice of ATC treatment 
has to be modified based on resectability and the 
lymphatic invasion of cancer.39
Conclusions
A history of RAI therapy was present in 7.7% of pa-
tients with ATC, and the number of patients with a 
history of RAI therapy did not change over time. 
The incidence of ATC in Slovenia probably de-
creased because of higher salt iodination. Patients 
are nowadays older and have less frequent lymph 
node metastases than in the past. The frequency of 
distant metastases did not change over time. The 
median survival of patients remains short. 
Acknowledgements
This research was funded by the Ministry of 
Education, Science and Sport of the Republic of 
Slovenia, grant number P3-0289. 
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