Radiation induced thyroid cancer: fundamental and applied aspects
Aim: To describe the epidemiology and pathology of thyroid cancer in Ukraine, and to perform the molecular analysis of genetic alterations more frequently found to be associated to papillary carcinomas (PTC) in a selected group of PTC. Materials and Methods: Relationship between the thyroid cancer i...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Cite this: | Radiation induced thyroid cancer: fundamental and applied aspects / M. Tronko, T. Bogdanova, L. Voskoboynyk, L. Zurnadzhy, V. Shpak, L. Gulak // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 200-204. — Бібліогр.: 22 назв. — англ. |
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Tronko, M. Bogdanova, T. Voskoboynyk, L. Zurnadzhy, L. Shpak, V. Gulak, L. 2018-06-19T10:31:08Z 2018-06-19T10:31:08Z 2010 Radiation induced thyroid cancer: fundamental and applied aspects / M. Tronko, T. Bogdanova, L. Voskoboynyk, L. Zurnadzhy, V. Shpak, L. Gulak // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 200-204. — Бібліогр.: 22 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138609 Aim: To describe the epidemiology and pathology of thyroid cancer in Ukraine, and to perform the molecular analysis of genetic alterations more frequently found to be associated to papillary carcinomas (PTC) in a selected group of PTC. Materials and Methods: Relationship between the thyroid cancer incidence and gender, age, and place of residence of subjects aged 0–18 years at the time of the Chernobyl accident (5427 subjects of thyroid cancer, among which 3996 (73.6%) were children aged 0 to 14 years at the time of the accident, and 1431 (26.3%) were adolescents aged 15 to 18 years was studied. Pathologically analyzed thyroid carcinomas were obtained from 640 patients (20–40 years old at the time of surgery and born before the Chernobyl accident), and from 90 patients (11–22 years old at the time of surgery and born after the accident). All patients were operated during 2006–2008. RET/PTC rearrangements and BRAFV600E mutation were analyzed in 35 cases of PTC. Results: A comparison between the thyroid cancer incidence rates in the 6 highest contaminated regions of Ukraine and in the other 21 regions shows the most significant difference between the rates for the last three years of follow-up, which confirms that a direct relationship is still present between the rise in thyroid cancer incidence and the post Chernobyl radiation exposure. Much lower incidence of thyroid cancer in subjects, who were born after the accident, additionally confirmed a direct relationship between the Chernobyl accident and thyroid cancer development at least in those who were aged up to 18 years at the time of the nuclear accident. Pathological results showed that with increasing latency the decrease has been noted in the percentage of PTC with solid structure, a decrease in invasive properties of tumors, as well as an increase in the percentage of PTC with papillary-follicular structure, encapsulated forms, and «small» carcinomas measuring up to 1 cm. Molecular-biological studies of PTC revealed more common RET/PTC1 and RET/PTC3 rearrangements (34.3% of cases), than BRAFV600E mutation (24%cases). Conclusion: After 22 years from the Chernobyl nuclear accident the number and incidence of thyroid cancer cases in Ukraine was steadily increased in the cohort of those who were children and adolescents at the time of the accident. Most common thyroid tumors (PTC) were characterized by significant changes in histological structure with increasing latency. PTC with any RET/PTC rearrangements had more aggressive behavior than BRAFV600E-positive tumors or PTC without gene alterations. The authors gratefully acknowledge the confirmation of diagnosis provided by the International Pathology Panel of the Chernobyl Tissue Bank: Dr. A. Abrosimov, Prof. T. Bogdanova, Prof. M. Ito, Prof. V. LiVolsi, Prof. J. Rosai and Prof. E.D. Williams. We gratefully acknowledge Prof. А. Pinchera, Prof. R. Elisei, and Dr. C. Romei from the Department of Endocrinology (Pisa University, Italy). This study was supported by grant from International Union Against Cancer (UICC). en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Radiation induced thyroid cancer: fundamental and applied aspects Article published earlier |
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Radiation induced thyroid cancer: fundamental and applied aspects |
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Radiation induced thyroid cancer: fundamental and applied aspects Tronko, M. Bogdanova, T. Voskoboynyk, L. Zurnadzhy, L. Shpak, V. Gulak, L. Original contributions |
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Radiation induced thyroid cancer: fundamental and applied aspects |
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Radiation induced thyroid cancer: fundamental and applied aspects |
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Radiation induced thyroid cancer: fundamental and applied aspects |
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Radiation induced thyroid cancer: fundamental and applied aspects |
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radiation induced thyroid cancer: fundamental and applied aspects |
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Tronko, M. Bogdanova, T. Voskoboynyk, L. Zurnadzhy, L. Shpak, V. Gulak, L. |
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Tronko, M. Bogdanova, T. Voskoboynyk, L. Zurnadzhy, L. Shpak, V. Gulak, L. |
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Original contributions |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Aim: To describe the epidemiology and pathology of thyroid cancer in Ukraine, and to perform the molecular analysis of genetic alterations more frequently found to be associated to papillary carcinomas (PTC) in a selected group of PTC. Materials and Methods: Relationship between the thyroid cancer incidence and gender, age, and place of residence of subjects aged 0–18 years at the time of the Chernobyl accident (5427 subjects of thyroid cancer, among which 3996 (73.6%) were children aged 0 to 14 years at the time of the accident, and 1431 (26.3%) were adolescents aged 15 to 18 years was studied. Pathologically analyzed thyroid carcinomas were obtained from 640 patients (20–40 years old at the time of surgery and born before the Chernobyl accident), and from 90 patients (11–22 years old at the time of surgery and born after the accident). All patients were operated during 2006–2008. RET/PTC rearrangements and BRAFV600E mutation were analyzed in 35 cases of PTC. Results: A comparison between the thyroid cancer incidence rates in the 6 highest contaminated regions of Ukraine and in the other 21 regions shows the most significant difference between the rates for the last three years of follow-up, which confirms that a direct relationship is still present between the rise in thyroid cancer incidence and the post Chernobyl radiation exposure. Much lower incidence of thyroid cancer in subjects, who were born after the accident, additionally confirmed a direct relationship between the Chernobyl accident and thyroid cancer development at least in those who were aged up to 18 years at the time of the nuclear accident. Pathological results showed that with increasing latency the decrease has been noted in the percentage of PTC with solid structure, a decrease in invasive properties of tumors, as well as an increase in the percentage of PTC with papillary-follicular structure, encapsulated forms, and «small» carcinomas measuring up to 1 cm. Molecular-biological studies of PTC revealed more common RET/PTC1 and RET/PTC3 rearrangements (34.3% of cases), than BRAFV600E mutation (24%cases). Conclusion: After 22 years from the Chernobyl nuclear accident the number and incidence of thyroid cancer cases in Ukraine was steadily increased in the cohort of those who were children and adolescents at the time of the accident. Most common thyroid tumors (PTC) were characterized by significant changes in histological structure with increasing latency. PTC with any RET/PTC rearrangements had more aggressive behavior than BRAFV600E-positive tumors or PTC without gene alterations.
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https://nasplib.isofts.kiev.ua/handle/123456789/138609 |
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Radiation induced thyroid cancer: fundamental and applied aspects / M. Tronko, T. Bogdanova, L. Voskoboynyk, L. Zurnadzhy, V. Shpak, L. Gulak // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 200-204. — Бібліогр.: 22 назв. — англ. |
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2025-11-24T16:07:16Z |
| last_indexed |
2025-11-24T16:07:16Z |
| _version_ |
1850850785132281856 |
| fulltext |
200 Experimental Oncology 32, 200–204, 2010 (September)
After 22 years from the Chernobyl accident the num-
ber of thyroid cancer cases in persons been children
and adolescents at the time of this catastrophe was
steadily increased in Ukraine, and 561 newly diagnosed
cases have been registered in 2008. An estimation of
Clinical-Morphological Register’s data by age at the
time of the accident shows that for the post-Chernobyl
period (1986–2008) 5427 cases of thyroid cancer have
been registered in the above age group, among which
3996 (73.6%) were children aged 0 to 14 years, and 1431
(26.3%) were adolescents aged 15 to 18 years at the
time of the accident. As well as in previous years, also
in 2006–2008 the highest thyroid cancer incidence was
registered in the 6 most contaminated northern regions
of Ukraine. In the cohort of those born in 1968–1986
and operated on in 2006–2008, thyroid cancer was
observed only in young adults aged 20–40 years, and
91.2% of them were represented by papillary carcino-
ma. These tumours were mainly with papillary, follicular
or papillary-follicular structure (70.4% of cases) and
presented with low levels of regional and distant metas-
tases. Thyroid cancer incidence between children and
adolescents born after the accident was much lower
than in patients born before the accident. Nevertheless
the pathological features of papillary carcinomas in
both groups were similar. Molecular-biological studies
showed that in papillary thyroid carcinomas RET/PTC1,
RET/PTC3, RET/PTCX rearrangements and BRAFV600E
mutations were detected. Papillary carcinomas with
RET/PTC rearrangements were characterized by more
prominent aggressiveness with respect to tumors with
BRAF mutation or without any genetic alterations.
MATERIAL AND METHODS
Statistical data were obtained from clinical-morpho-
logical Register of the State Institution «Institute of En-
docrinology and Metabolism of the Academy of Medical
Sciences of Ukraine» [1]. Pathologically studied thyroid
carcinomas were obtained from 640 patients who were
20–40 years old at the time of surgery and born before
the Chernobyl accident, and from 90 patients who were
11–22 years old at the time of surgery and born after
the accident. All patients were treated at the Hospital
of the State Institution «Institute of Endocrinology and
Metabolism of the Academy of Medical Sciences of
Ukraine» during 2006–2008. All patients gave informed
written consent. Studies were performed according to
the rules of local Ethical Committee.
These cases were analyzed together with 1342 cas-
es of thyroid carcinomas of patients who were
4–36 years old at the time of surgery and born before
the accident, and 118 cases of thyroid carcinomas
RADIATION INDUCED THYROID CANCER: FUNDAMENTAL AND
APPLIED ASPECTS
M. Tronko1,*, T. Bogdanova1, L. Voskoboynyk1, L. Zurnadzhy1, V. Shpak1, L. Gulak2
1Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Vyshgorodskaya
str. 69, Kyiv 04114, Ukraine
2National Cancer Institute of Ministry of Health of Ukraine, Lomonosova str. 33/43, Kyiv 03022, Ukraine
Aim: To describe the epidemiology and pathology of thyroid cancer in Ukraine, and to perform the molecular analysis of genetic alterations
more frequently found to be associated to papillary carcinomas (PTC) in a selected group of PTC. Materials and Methods: Relationship
between the thyroid cancer incidence and gender, age, and place of residence of subjects aged 0–18 years at the time of the Chernobyl
accident (5427 subjects of thyroid cancer, among which 3996 (73.6%) were children aged 0 to 14 years at the time of the accident, and
1431 (26.3%) were adolescents aged 15 to 18 years was studied. Pathologically analyzed thyroid carcinomas were obtained from 640
patients (20–40 years old at the time of surgery and born before the Chernobyl accident), and from 90 patients (11–22 years old at the
time of surgery and born after the accident). All patients were operated during 2006–2008. RET/PTC rearrangements and BRAFV600E-
mutation were analyzed in 35 cases of PTC. Results: A comparison between the thyroid cancer incidence rates in the 6 highest contami-
nated regions of Ukraine and in the other 21 regions shows the most significant difference between the rates for the last three years of
follow-up, which confirms that a direct relationship is still present between the rise in thyroid cancer incidence and the post Chernobyl
radiation exposure. Much lower incidence of thyroid cancer in subjects, who were born after the accident, additionally confirmed a direct
relationship between the Chernobyl accident and thyroid cancer development at least in those who were aged up to 18 years at the time
of the nuclear accident. Pathological results showed that with increasing latency the decrease has been noted in the percentage of PTC
with solid structure, a decrease in invasive properties of tumors, as well as an increase in the percentage of PTC with papillary-follicular
structure, encapsulated forms, and «small» carcinomas measuring up to 1 cm. Molecular-biological studies of PTC revealed more common
RET/PTC1 and RET/PTC3 rearrangements (34.3% of cases), than BRAFV600E mutation (24%cases). Conclusion: After 22 years from
the Chernobyl nuclear accident the number and incidence of thyroid cancer cases in Ukraine was steadily increased in the cohort of those
who were children and adolescents at the time of the accident. Most common thyroid tumors (PTC) were characterized by significant
changes in histological structure with increasing latency. PTC with any RET/PTC rearrangements had more aggressive behavior than
BRAFV600E-positive tumors or PTC without gene alterations.
Key Words: Chernobyl nuclear accident, thyroid cancer, papillary carcinomas.
Received: July 19, 2010.
*Correspondence: E-mail: tb@viaduk.net
Abbreviations used: EC — extracellular domain; FTC – follicular
carcinomas; PTC — papillary carcinomas; TK — tyrosine kinase
Exp Oncol 2010
32, 3, 200–204
Experimental Oncology 32, 200–204, 2010 (September) 201
of children and adolescents who were born after the
accident and described in our previous study [2].
The pathological diagnosis was made according
to the WHO Histological Classification [4]. Most of the
cases were additionally reviewed by the International
Pathology Panel, established in the framework of the
Tissue Bank Project [5]. The diagnosis of thyroid car-
cinoma was confirmed in all cases.
The papillary carcinomas (PTC, n = 35) were also
studied by molecular biology approach. In particular,
total RNA was extracted from the frozen thyroid tumors
and normal tissues, obtained from Chernobyl Tissue
Bank (http://www.chernobyltissuebank.com). The mean
age at surgery of this selected group of patients was
21 ± 5 years. The mean latency period was 14 ± 1 years.
For RET/PTC analysis RT-PCR and southern blot
was used as previously described [6]. BRAFV600E muta-
tions were studied by direct sequencing of exon 15 [7].
Real-time RT-PCR method was used to measure the
expression levels of the tyrosine kinase domain (TK)
and extracellular domain (EC) of the RET gene [8]. Tar-
get gene mRNA levels were expressed as 2-ΔCt, where
ΔCt = Ct of target gene – Ct of reference gene [7]. The ratio TK/EC
was calculated for all studied samples. The value of
TK/EC values higher than 2 suggested the presence
of a RET/PTC rearrangement. Molecular biological
investigations have been carried out in collaboration
with the University of Pisa (Italy).
RESULTS AND DISCUSSION
Epidemiology and statistics. 1556 newly diagnosed
thyroid cancer cases have been reported in Ukraine dur-
ing the period of 2006–2008. An estimation of Register’s
data by age at the time of the accident showed that for all
post-Chernobyl period (1986–2008) 5427 cases of thy-
roid cancer have been registered in the above age group,
among which 3996 (73.6%) were children aged 0 to 14
years at the time of the accident, and 1431 (26.3%) were
adolescents aged 15 to 18 years (Tables 1, 2).
Undoubtedly, this steady increase in thyroid cancer
cases may be to some extent associated with a gradual
increase in the age of the cohort under study for the
period 1986–2008. At the same time, a comparison
between the thyroid cancer incidence rates in the six
highest contaminated regions of Ukraine and in the
other regions of Ukraine shows the most significant
difference between the rates for the last three years of
follow-up, which confirms that a direct relationship is
still present between the rise in thyroid cancer incidence
and the post Chernobyl radiation exposure (Tables 1, 2).
At the time of surgery total of 5732 patients who
were 4–40 years at surgery (5427 were born before,
and 305 – after the Chernobyl accident) were included
in the Register for the period of 1986 to 2008. All 1556
cases revealed during three last years in patients
who were born before the accident have been de-
tected in young adults who had surgery at the age of
20–40 years. The incidence per 100,000 significantly
increased during this period, especially in the most
contaminated 6 north regions of Ukraine (7.87) in
comparison with less contaminated 21 regions (2.87).
If we consider the incidence among children, ado-
lescents and young adults born before and after the
Chernobyl accident separately, it appears that in children
born before the accident who were up to age of 15 years
at the time of surgery, the incidence was highest in 2000
(5.21 per 100,000 in most contaminated regions). Be-
ginning from 2001, these children have gone over to the
category of adolescents. At the same time, the incidence
in children born after the accident were and remained
much lower (for example, in 2000 — 0.13; in 2008 — 0.21).
A similar tendency was also noted when comparing
the incidence in adolescents and young adult patients.
For example, in 2008 in young adults born before the
accident the incidence in most contaminated regions
was 8.09, but in young adults born after the accident —
1.91. These data represent an additional evidence of a
direct relationship between the Chernobyl accident and
thyroid cancer development at least in those who were
aged up to 18 years at the time of the nuclear accident.
Pathology. The histological examination of 640
thyroid carcinomas diagnosed between 2006 and
2008 showed that 91.2% of cases were represented
by PTC. It is of interest that the percentage of follicular
Table 1. Number of thyroid cancer cases and incidence per 100,000 children population in 1986* by year, sex and region
Year
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
Number (F) 4 9 7 18 24 32 61 54 80 92 100 106 135 162 149 231 211 188 236 239 306 333 370
Number (M) 4 2 4 8 17 15 27 30 29 33 43 31 38 59 38 55 52 54 42 60 65 71 72
Total number 8 11 11 26 41 47 88 84 109 125 143 137 173 221 187 286 263 242 278 299 371 404 442
Total incidence 0.07 0.10 0.10 0.23 0.37 0.42 0.79 0.75 0.97 1.12 1.28 1.22 1.54 1.97 1.67 2.55 2.35 2.16 2.48 2.68 3.31 3.61 3.95
6 regions incidence 0.14 0.00 0.14 0.38 0.76 1.10 2.38 2.10 2.62 2.90 3.33 2.76 3.81 5.14 4.86 6.81 6.19 5.05 5.33 5.76 7.24 7.86 7.95
21 regions incidence 0.05 0.12 0.09 0.20 0.27 0.27 0.42 0.44 0.59 0.70 0.80 0.87 1.02 1.24 0.92 1.57 1.45 1.49 1.82 1.96 2.41 2.63 3.02
Note: *Those aged 0–14 years at the time of the Chernobyl accident
Table 2. Number of thyroid cancer cases and incidence per 100,000 adolescents population in 1986* by year, sex and region
Year
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
Number (F) 9 9 10 9 19 19 26 42 37 60 46 51 70 61 56 74 71 74 76 96 85 96 102
Number (M) 2 6 2 4 2 4 9 7 9 8 10 11 11 9 14 15 22 13 7 12 18 21 17
Total number 11 15 12 13 21 23 35 49 46 68 56 62 81 70 70 89 93 87 83 108 103 117 119
Total incidence 0.42 0.57 0.45 0.49 0.79 0.87 1.32 1.85 1.74 2.57 2.11 2.34 3.06 2.64 2.64 3.36 3.51 3.28 3.13 4.08 3.89 4.42 4.49
6 regions incidence 0.19 1.15 0.00 0.58 1.15 1.54 1.92 1.92 2.12 4.23 2.69 3.65 5.38 3.27 5.00 6.15 6.73 7.12 5.38 7.05 8.85 9.04 8.65
21 regions incidence 0.47 0.42 0.56 0.47 0.70 0.70 1.17 1.83 1.64 2.16 1.97 2.02 2.49 2.49 2.07 2.68 2.72 2.35 2.58 3.24 2.68 3.29 3.47
Note: *Those aged 15–18 years at the time of the Chernobyl accident
202 Experimental Oncology 32, 200–204, 2010 (September)
carcinomas (FTC) was increased from 3.0% in cases
diagnosed in 1990–1995 to 6.4% in those diagnosed in
2006–2008. This finding suggests that FTC incidence
might be related both to an older age at diagnosis and
to a longer latency period when compared to PTC.
However, the relatively small number of FTC does not
allow any definitive conclusions on this matter.
The ratio of PTC subtypes in young adults for the
2006–2008 period confirmed our previous data concern-
ing an inverse relationship between the latency period
and the prevalence of more aggressive variants (i.e. solid
variant) [2]. Also in the Ukrainian series we observed
the decrease in the percentage of solid variant from
21.4% in 1990-1995 to 6.3% in 2006–2008 (р < 0.01
by χ2-test), and an increase in the percentage of typical
papillary and mixed variants from 21.4% in 1990–1995 to
34.4% in 2006–2008, and from 21.4% in 1990–1995 to
43.0 % in 2006–2008 respectively (р < 0.05 by χ2-test).
The structural combinations of mixed variant have also
changed over time: the percentage of tumors with solid-
follicular structure was substantially decreased (from
66.6% in 1990–1995 to 21.1% in 2006–2008, р < 0.01
by χ2-test), while the percentage of tumors with papil-
lary-follicular structure was increased (from 16.7% in
1990–1995 to 46.2% in 2006–2008, р < 0.01 by χ2-test).
An analysis of invasive properties of PTC has revealed
two main relationships: age and time dependences.
Extrathyroid tumor spreading to soft tissues adjacent
to the thyroid, which allowed to refer such a tumor to T3
category according to the 6th edition, was more often
detected among children compared to adolescents,
and especially young adults (64.8; 38.9 and 24.1%,
respectively). However, when we pooled together all
age groups, a marked decrease in the percentage of
tumors with extrathyroidal spreading was observed in
those cases with a longer latency period varying from
61.2% in cases diagnosed in 1990–1995 to 16.3% in
those diagnosed in 2006–2008 (р < 0.001 by χ2-test).
A similar change was observed when the prevalence
of regional metastases to cervical lymph nodes was
considered. Lymph node metastases in the neck were
most often reported among children who had surgery
at the age up to 15 years (68.6%), while the percentage
of these metastases was decreasing with the increase of
the latency period varying from 58.2% in 1990–1995 to
28.8% in 2006–2008 (р < 0.01 by χ2-test). The analysis
of cases with distant metastases to lungs has shown a
similar tendency. Particular attention should be given to
the fact that for the last period of follow-up (2006–2008)
only 1.9% out of 584 PTC cases showed distant metas-
tases to lungs. From our standpoint, this fact was likely
favored both by the above change in the PTC structure,
associated with the increase of both the patients’ age
and latency period of tumor development.
Other possible reasons to explain this change of the
biological behavior of PTC might be related to two new
interesting findings: a) The significant increase in the
percentage of completely encapsulated tumors found in
the last years (30.5% in 2006–2008) with respect to that
observed previously (7.4% in 1990–1995, р < 0.001 by
χ2-test); b) The progressive increase of «small» tumors
with the biggest diameter up to 1 cm (microPTC): from
4.1% in 1990–1995 to 26.0 % in 2006–2008 (р < 0.001
by χ2-test). Such increase of the percentage of mi-
croPTCs is undoubtedly the result of an intensification
of screening examinations [9] and improvement of the
diagnostic facilities (i.e. modernization of ultrasound
equipment and wide use of fine-needle aspiration
biopsy) [10, 11].
A comparison of different histotypes of thyroid
carcinomas in children and adolescents born before
and after the Chernobyl accident, shows that in both
groups the PTC was the prevalent histotype (93.0%
and 84.1% respectively). However, it should be noted
that in patients born after the accident (i.e. in 1987 and
later) the percentage of FTC was notably higher (4.8%
and 12.5%, respectively, р < 0.01 by χ2-test).
Invasive properties of PTC are similar in both groups
either when considering the extrathyroid spreading
(54.8% in children and adolescents together born
before the accident, and 48.2% in those born after
the accident) or the presence of regional lymph node
metastases (60.0% and 54.8%, respectively). The
percentage of distant metastases to lungs (22.7%
and 9.5%, respectively, р < 0.001 by χ2-test) was sig-
nificant lower in patients born after the accident, but
this finding might be due to an early diagnosis as well
as to the higher percentage of microPTC in this group
(6.3% and 13.7%, respectively, р < 0.05 by χ2-test).
Molecular-biological study. About 15 different
isoforms of RET/PTC rearrangements were described
in the literature till now, but the most common among
them are RET/PTC1 and RET/PTC3 alterations [12, 13].
RET/PTC rearrangements (RET/PTC1, RET/PTC3
and unknown RET/PTCX) and BRAFV600E point mutations
have been screened in 35 cases of post-Chernobyl
Ukrainian papillary carcinomas. As shown in Table 3,
the most common RET/PTC1 and/or RET/PTC3 rear-
rangements were detected in 12 of 35 (34.3%) PTC,
one of which showed the simultaneous expression of
both, RET/PTC1 and RET/PTC3. It should be noted that
in another case RET/PTC3 was present in association
with BRAFV600E mutation. When the prevalence of the
two types of rearranged RET oncogenes was analyzed,
we found that RET/PTC3 was more frequent than RET/
PTC1: 8/35 (22.9%) vs. 5/35 (14.3%), respectively. In
general, in 18 from 35 PTC (51.4%) the presence of
rearranged oncogenes RET/PTC was shown.
Table 3. Gene alterations in post-Chernobyl thyroid papillary carcinomas
PTC, % (n = 35)
RET/PTC rearrangements 51.4 (18/35)
RET/PTC1 11.4 (4/35)
RET/PTC3 17.1 (6/35)
RET/PTC1+ RET/PTC3 2.9 (1/35)
RET/PTC3 + BRAF 2.9 (1/35)
RET/PTCX 17.1 (6/35)
BRAFV600E mutation (including one case with RET/PTC3
rearrangenemt)
24.0 (6/25)
Total 68.6 (24/35)
BRAFV600E point mutations have been discovered as
the most common genetic alteration in sporadic adult
papillary thyroid carcinomas [7, 19]. Our previous stud-
Experimental Oncology 32, 200–204, 2010 (September) 203
ies of post-Chernobyl PTC in children and adolescents
of Ukraine revealed a low frequency of such alterations
[2, 15, 20]. Present study showed, that BRAFV600E point
mutations in patients with mean age 21 years, and
mean latency 14 years were found in 6 PTC out of 25
(24%). This is higher than in children and adolescents,
and confirmed previous conclusion, that frequency of
BRAF mutations are increasing with age of patients [2,
18, 21]. Among them coexistence of RET/PTC3 and
BRAF alterations, as mentioned above, was detected
in one of the tumors. Any gene alterations in normal
surrounding tissues have not been detected.
The correlation between specific genetic alterations
and histological structure of PTC was observed. In
tumors with RET/PTC1 rearrangements the majority of
cases (4/5, 80.0%) were with typical papillary structure.
In contrary, solid variant of PTC was most specific for
carcinomas with RET/PTC3 alterations (6/8, 75.0%).
Among them tumor presented coexistence of both RET/
PTC1 and RET/PTC3 alterations had papillary structure.
This study confirmed our previous results [2, 14, 15] and
the results of other studies [13, 16–18] showing the as-
sociation of RET/PTC1 with typical papillary variant of
PTC, and RET/PTC3 with solid one. It should be noted
that the correlation between unknown RET/PTCX rear-
rangements and histological features was not revealed.
All main histological variants (follicular, papillary, solid
and mixed) were represented in this group of PTC.
The majority of BRAF positive tumors (4/6) were of
typical papillary variant, one case was FTC, and one (with
both BRAF mutation and RET/PTC3 rearrangement)
was papillary-solid. So, the majority of PTC with BRAF
mutation had typical papillary structure, what completely
agree with our previous results [2, 15, 20, 21].
One PTC in our study had both RET/PTC3 and
BRAFV600E mutations. This tumor had mixed papillary-
solid histological structure. It should be noted that such
two genetic events in the same tumor was not detected
in our previous studies of Ukrainian post-Chernobyl
PTC [15, 20, 21], but were described by other authors
as very rare event in PTCs [22].
The half of tumors without gene alterations were
characterized by mixed histological papillary-follicular
structure.
It was shown, that signs of extrathyroid invasion,
multifocal growth, blood vessels invasion, regional and
distant metastases were present mainly in papillary
carcinomas with RET/PTC rearrangements, whereas
they were practically absent in tumors with BRAFV600E
mutations (Figure). The invasion of tumor cells to lym-
phatic vessels was revealed in the majority of PTCs,
and this characteristic was not related to the presence
of gene alterations.
According to some publications [13, 16] BRAF-
positive papillary carcinomas had higher incidence
of extrathyroid invasion and lymph node metastases,
higher tumor stage, and patients with such carcinomas
had less favorable prognosis. However, other obser-
vations carried out on post-Chernobyl PTCs did not
reveal such association [15, 20, 21]. Maybe, it could
be due to the difference of the age of the patients
and to the fact that aggressiveness of BRAF mutants
increases with the age of patients. Our results indicate
that in young adults (mean age 21 years) prognosis for
patients with BRAF-positive papillary carcinomas is
more favorable with respect to other PTCs, both with
RET/PTC rearrangements and without them.
Extrathyroid invasion
0
10
20
30
40 Multifocal growth
0
10
20
30
40
Lymphtic vessels invasion
0
20
40
60
80
100 Blood vessels invasion
0
10
20
30
40
50
Lymph nodes metastases
0
20
40
60
80
100 Distant metastases
into lung
0
10
20
30
40
50
ret/ptc braf no
alterations ret/ptc braf no
alterations
ret/ptc braf no
alterations ret/ptc braf no
alterations
ret/ptc braf no
alterations ret/ptc braf no
alterations
Figure. Invasive properties of papillary thyroid carcinomas with
RET/PTC rearrangements, BRAFV600E mutations, and without
any alterations
In summary, on the bases of these observations, it
appears that papillary carcinomas with any RET/PTC
rearrangements had a more aggressive behavior than
BRAFV600E-positive tumors or PTC without gene alterations.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the confirma-
tion of diagnosis provided by the International Pathol-
ogy Panel of the Chernobyl Tissue Bank: Dr. A. Abrosi-
mov, Prof. T. Bogdanova, Prof. M. Ito, Prof. V. LiVolsi,
Prof. J. Rosai and Prof. E.D. Williams. We gratefully
acknowledge Prof. А. Pinchera, Prof. R. Elisei, and
Dr. C. Romei from the Department of Endocrinology
(Pisa University, Italy). This study was supported by
grant from International Union Against Cancer (UICC).
204 Experimental Oncology 32, 200–204, 2010 (September)
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