Thyroid Cancer in infants and adolescents after Chernobyl
Christoph Reinersa, Yuri E. Demidchikb, Valentina M. Drozdc, Johannes Bikoa
a
Clinic and Policlinic of Nuclear Medicine, University of Wuerzburg, Josef-Schneider-Str. 2,
97080 Wuerzburg, Germany
b
Republican Center for Thyroid Tumors, Minsk, Belarus
Belarussian-German Fonds “Arnica” for Follow-Up of Childhood Thyroid Tumors, Minsk,
c
Belarus
Prof. Dr. Christoph Reiners
Clinic and Policlinic for Nuclear Medicine
University of Würzburg
Josef-Schneider-Str. 2
D-97080 Würzburg
Tel. +49 931 201 35868
Fax +49 931 201 35247
E-mail: reiners@nuklearmedizin.uni-wuerzburg.de
Abstract
Studies in children medically exposed to external irradiation more than 50 years ago
revealed a considerably increased risk for thyroid cancer. Similarly, a strongly agedependent risk for thyroid cancer was observed in the Japanese population after the atomic
bomb explosions with the highest risk in a group of children below age of 10. After the
Chernobyl accident, children from Belarus living in the Gomel region received mean thyroid
doses by radioactive fallout higher by a factor of approximately 2 as compared to the
survivors of the atomic bomb explosions. This lead to a radiation related increase of thyroid
cancer incidence in children and adolescents with the highest incidence in age group 0-4
years up to now totally amounting to approximately 5000 cases.
For screening of thyroid cancer in children, high resolution ultrasound is the method of choice
which has to be complemented by fine-needle aspiration biopsy in suspicious cases.
Diagnostic criteria for malignancy in childhood thyroid cancer by ultrasound are
hypoechogenicity and irregularity of the outline, subcapsular location of lesions and
increased peri-intranodular vascularisation.
The treatment strategy for thyroid cancer in children does not differ substantially from the
approach used in adults. Pulmonary treatment consists of thyroidectomy and lymph node
dissection. Careful and complete removal of the lymph nodes is of great clinical relevance in
children because of very frequent node involvement (between 40 and 90%). Because of the
high prevalence of lymph node metastases, ablation of thyroid remnants is mostly indicated
in children with thyroid cancer. Distant metastases which need higher activities of radioiodine
are less frequent with 10-20%. Even in advanced cases of childhood thyroid cancer, longlasting remissions can be achieved. A specific finding in children is disseminated, milliary
lung metastases with intense radioiodine uptake. In this situation, pulmonary fibrosis may be
a severe side-effect so that the indication for repeated courses of radioiodine therapy has to
be decided thoroughly. With respect to side-effects of radioiodine therapy, the risk of
developing breast cancer has to be taken into account seriously since especially the female
2
breast is exposed to a relatively high radiation dose. Generally, young patients treated with
high activities of radioiodine should be carefully followed up during their whole lifespan.
Keywords
Thyroid cancer, radiation exposure, epidemiology, clinical presentation, diagnostic criteria,
surgery, radioiodine therapy, side-effects
3
Experiences from the Past
It is known since now more than 50 years, that exposure to external radiation is associated
with harmful effects to the thyroid, such as hypothyroidism, thyroid autoimmunity, induction of
thyroid nodules and thyroid cancer [1]. There are several longitudinal cohort studies which
provide clear data on the long-term risks for thyroid cancer and other neoplasms after thyroid
exposure to radiation [2]. The excess relative risk after medical irradiation per Gy amounts to
approximately 4.5 (Tab. 1) as has been shown by a comprehensive review of E. Ron et al.
[3].
Some other examples include the long-term follow-up of survivors from atomic bomb
detonations in Japan [4,5]. With respect to age-dependence, Thompson et al. [6] showed,
that there is a very significant increase of thyroid cancer risk in the young age-group of 0-9
years, a lesser, but highly significant risk in adolescents below age of 20, however no
significant increase of thyroid cancer risk in adults above the age of 20 (Tab. 2). Using model
calculations, Zanzonico showed, that age dependent thyroid dose factors for I-131 vary from
36 in newborns to 1.4 in adults [7]. Because of this age-relation, especially small children
should be most efficiently protected against the possible hazards of ionizing radiation.
Thyroid Cancer after Medical Exposure to Radioiodine
Comprehensive data from a Swedish longitudinal cohort study in 36.792 patients exposed to
diagnostic activities of radioiodine (I-131) seem to indicate a small, but significant increase of
thyroid cancer. However, if the analysis was performed separately in the two subgroups,
which were referred for diagnosis because of suspicion of a thyroid tumor (n=11.015) and for
other reasons respectively (n=24.010), the increased risk was only seen in those who
already were suspicious to harbor a thyroid tumor [8].
Concerning the therapeutic application of radioiodine, data from longitudinal follow-up in
10.522 patients from Sweden, who had been treated with radioiodine between 1950 and
4
1975 are available too [9]. In this group, the incidence of thyroid cancer after radioiodine
therapy for benign thyroid disorders was not increased.
The Chernobyl Accident
During the night from 25 to 26 April 1986, the most severe reactor accident happened at the
nuclear power plant, Chernobyl 30 km south of the border of the Ukraine and Belarus. The
reactor core exploded and caught fire, and the fire could not be extinguished until 9 May
1986. Due to the burning graphite, enormous amounts of radioactivity were released during
the first 10 days. According to recent calculations, approximately 12x1018 Bq (~0.3 billion Ci)
of radioactivity was released, including 1.8x1018Bq of
131
I. The radioactivity was transported
with the prevailing winds from the northern parts of the Ukraine to Belarus and the western
parts of Russia and later to Scandinavia and parts of Western Europe. Belarus has been
most heavily contaminated, with 70% of the released activity. Extremely high contaminations
have been found in people evacuated from the near surrounding of the Chernobyl Power
Plant and in the inhibitants of the Gomel area with corresponding thyroid doses by
radioiodine isotopes (Tab. 4).
Epidemiological Studies after Chernobyl
According to a comprehensive review published by a working group of WHO on the occasion
of the 20th anniversary of the Chernobyl accident, the main tremendous health effect of
radiation from the accident observed today is a dramatic increase of the incidence of thyroid
cancer in persons exposed as young people [14]. This increase was observed first in the
early 1990s in Belarus and continues until now in the most contaminated areas of Belarus,
Ukraine and the Russian Federation [13,14,17,18,19]. To illustrate this, figure 1 shows the
temporal trends of childhood (0-14 years), adolescent (15-18 years) and adult (19-34 years)
thyroid cancer in the general population of Belarus following the accident. By 1995, the
incidence of childhood thyroid cancer had increased to four per 100 000 per year compared
to 0.03-0.05 cases per 100 000 per year prior to the accident. As those who were children at
5
the time of the accident have aged (by 2002, even the very youngest had reached
adulthood), the childhood thyroid cancer rates have declined to near zero and parallel
increases in the incidence of thyroid cancer in adolescents and slightly later in young adults
have been seen.
The number of thyroid cancer cases diagnosed in Belarus, Ukraine and in the four most
contaminated regions of Russia during 1986-2002 among those who were children (< 15) or
adolescents (15-17) at the time of the Chernobyl accident is presented in table 5. Altogether
close to 5000 cases were observed in the three countries. Of those, 15 are known to have
been fatal up to now.
At the time of the Chernobyl accident, it was supposed, that radioisotopes of iodine had a
lesser carcinogenic potential than external exposure by X-ray or photon radiation [20].
However, the excess relative risks derived in the case-control and cohort studies available up
to now show, that the risk for thyroid cancer after external exposure by radioiodine is very
similar to the very well-known risks after internal exposure (see preceding chapter). There is
some indication, that iodine deficiency at the time of exposure may increase the risk of
developing thyroid cancer [21,22]. On the other hand, prolonged stable iodine
supplementation in the years after exposure may reduce this risk [14]. Experiences from
Poland prove, that the timely preventive application of a relatively high dose of stable iodine
(50 mg) to children could reduce the risk to develop thyroid cancer after exposure to
Chernobyl fallout very effectively [23].
It has been claimed that malignant thyroid tumors after external irradiation typically present
as papillary cancers in more than 85% of exposed children and adolescents [3,24,25].
However, Samaan et al. [26] showed, when comparing two cohorts of thyroid cancer patients
with and without a history of head and neck irradiation as children, that the proportion of
papillary cancers in those two cohorts was not different with 87% and 84%, respectively.
6
Comparison with other data from the literature proves [27], that papillary histology per se is
typical for thyroid cancer in childhood and adolescents (Tab. 6).
According to Samaan’s study, bilateral lobe involvement (51%) and cancer not limited to the
thyroid gland (70%) seemed to be characteristic for thyroid cancer after external irradiation
[26]. This observation however could not be replicated by the observations which have been
made in children with radiation induced thyroid cancer after Chernobyl (Tab. 6). Obviously,
tumor extension and a prevalence of lymph node and distant metastases is associated
inversely with age at the time of radiation exposure in children after Chernobyl [42,43].
According to the literature, there may be some differences in the molecular biology of
radiation induced and non radiation-dependent thyroid cancer, particularly with regard to
RET-PTC rearrangements and BRAF-mutations [44,45]. However, most of the differences
observed seem to be related to age-effects (the mean age of children with thyroid cancer
after radiation exposure is usually considerably lower as the mean age of childhood thyroid
cancer patients without exposure to radiation). Using most recent micro-ray techniques, a
radiation-specific genetic signature have been described in a small group of Chernobyl
cancer cases as compared to control cases from France [46].
To summarize epidemiology of thyroid cancer after Chernobyl, the following conclusions can
be drawn according to a WHO expert group [14]:
-
Proven radiation related increase of thyroid cancer incidence in children and
adolescents (total number of cases approximately 5.000, highest incidence in agegroup 0-4).
-
No difference in risk between males and females.
-
Thyroid cancer increase in adults unclear (not dose-related).
-
Data are compatible with experience of the past after external exposure.
-
Projected number of cases for 50 years (Belarus) 15.000 (uncertainty range 5.00045.000; increase 80% of rough baseline)
-
Confounders are genetic factors, nutritional iodine status and screening.
7
Childhood thyroid cancer in Belarus
Ultrasound screening in Belarus
Using high resolution ultrasound scanners with 7.5 MHz probes, thyroid nodules with a
diameter of 5 mm can be detected. Screening programs in heavily contaminated areas of
Belarus revealed prevalences of thyroid cancer in children of 0.6% in 1990 and 0.3% in 1993
[46]. For comparison, the expected prevalence in the western world without radiation
exposure is approximately 0.15%. Diagnostic criteria (Tab. 7) for malignancy in childhood
thyroid cancer patients are nodule size, hypoechogenicity and irregularity of the outline,
subcapsular location of the lesion and increased peri-intranodular vascularisation [47].
Surgical Treatment in Belarus
From August 1985 to October 2005, 757 consecutive patients aged less than 15 years
underwent surgery and were followed-up in the Thyroid Cancer Center Minsk, Belarus [48].
Of them 4 (0.5%) children suffered from hereditary medullary carcinomas. As this type of
malignancy is pathogenetically different from the majority of pediatric thyroid tumors and not
related to radiation exposure, these cases were not included in the analysis. In addition one
patient with papillary carcinoma refused therapy and was also excluded from the evaluation.
Among the remaining 752 patients, radiation history was documented in 686 (91.2%)
individuals, including 661 (87.9%) children of residents of Belarus born before the Chernobyl
disaster, 20 (2.7%) cases exposed in utero (9 months period from the date of accident) and 5
(0.7%) patients previously treated for malignant lymphoma with chemotherapy followed by an
external beam therapy.
The second group consisted of 66 (8.8%) patients who had no history of radiation exposure.
The majority of them (62 patients) were born after the Chernobyl Power Plant disaster (the
accepted date from January 31, 1987). Four children with sporadic thyroid carcinomas had
developed cancer before the accident.
8
All the patients underwent surgery, mostly total thyroidectomy with simultaneous selective
neck dissection, and were maintained on levothyroxine suppressive therapy with a mean
dose of 2.0-2.5 µg/kg of body weight. Radioiodine therapy for thyroid remnants or lung
metastases was performed in 464 (61.7%) cases.
It is necessary to note that patients with sporadic carcinomas have been subjected on
average to the more aggressive surgical interventions because since 1998 the standard
operation includes total thyroid removal, neck dissection and precise lymph node mapping
(Tab 8).
The tumors were classified according to TNM UICC, 6th edition [49].
At diagnosis, most patients had solitary, usually asymptomatic tumors measuring less than 2
cm in the largest diameter corresponding to T1 stage (n=548, 72.9%) with a very high
frequency of lymph node metastases (n=623, 69.6%). Microcarcinomas with a diameter of
less than 1cm were detected in 278 (37.0%) cases.
Comparison of patients with radiogenic or sporadic thyroid cancer did not reveal statistically
significant differences between the two groups in the distribution of tumor size, histological
types or TNM stages (Tab. 9).
Symptoms at presentation were mainly caused by the large thyroid nodules or enlarged
lymph nodes. Neck mass ores or discomfort was a common complaint registered in 134 of
163 (82.2%) patients with clinical manifestations. Sporadic thyroid cancers appeared to be
significantly less symptomatic than radiogenic malignancies (Tab. 8).
During follow-up, recurrent disease was diagnosed in 204 (27.1%) of the patients. The main
sites of recurrence were the lung or lymph nodes whereas others (thyroid remnants, bone,
soft tissue or CNS) were uncommon and usually associated with positive neck nodes or
pulmonary metastases.
Perhaps because of the different follow-up periods, patients with radiogenic carcinomas had
a higher rate of recurrence as compared to sporadic cases but no significant difference was
found in the frequency of local relapse or distant metastases for these groups (Tab. 8)
9
The relatively common lymph node relapses in radiogenic cases were likely due to the
prevalence of less aggressive surgical procedures in the early years after the Chernobyl
disaster.
The disease-free interval ranged widely between 0 and 213 months after the date of primary
surgery without significant differences between radiogenic and sporadic cases. The observed
10-year survival was 99.5% for the entire series, including 99.5% and 99.7% in patients with
radiogenic and sporadic carcinomas, respectively [48].
Radioiodine therapy in Germany
Starting with April 1993, a joint Belarussian-German project on the combined treatment with
surgery and radioiodine has been launched. Thyroid surgery was performed in the Center for
Thyroid Tumors in Minsk, Belarus [41,48], and radioiodine therapy followed in Germany at
the Universities of Essen (until the end of 1994) and afterwards the University of Würzburg
[50].
Selection criteria for treatment were advanced disease (local invasiveness, lymph node
and/or distant metastases). Here the results of combined treatment in this high risk group will
be presented. The follow-up period ends with December 2007 (comprising now 14 years).
Between April 1st 1993 and December 31st 2007, 247 children from Belarus with most
advanced stages of thyroid cancer were selected for treatment in Germany (Tab. 10). Totally
1053 courses of I-131 therapy were applied during the treatment period.
42% of the children originated from the heavily contaminated Gomel region. The mean age
of the children at the time of the reactor accident was 2.6  2.2 years (78% of the children
were below age of 5). Their mean age at the time of surgery ranged from 7 - 19 years with a
mean age of 13.4 ± 3.1 years. This corresponds to a mean latency time of approximately 10
years; the shortest time interval between exposure and surgery was 3.2 years. 60% of the
10
children were female, 40% male. 99% of the cancers were typed histologically as papillary
and 1% as follicular carcinomas (Tab. 10).
62% of the cases selected for treatment in Germany because of the aggressiveness of
tumors had to be classified as stage pT4. In 96% of the cases lymph node metastases and in
42% of the children distant metastases had been detected. With the exception of two cases
with secondaries to the bone, distant metastases were localized in the lungs (among those
cases one child with metastases to lungs and brain). Nearly all of the cases with lung
metastases presented with disseminated miliary spread, whereas only 4% of the children
showed localized nodular lesions. Only 53% of the children with lung metastases detectable
by I-131 scanning showed positive thorax X-rays; this proportion was considerably with 82%
higher for high resolution computed tomography. In 44 of the 247 children radioiodine
treatment had been performed previously with different activities in Minsk (mainly low
activities up to 1 GBq) and Italy; 19 of the children had been irradiated percutaneously with
mainly low radiation doses (up to 20 Gy). In 6 children chemotherapy with different
substances (e.g. bleomycin) had been performed in Minsk.
Diagnosis and treatment protocol
Generally, the diagnosis and treatment protocol for children was very similar to the protocol
for children was very similar to the protocol used in adults.
The diagnostic protocol included ultrasonography and scintigraphy of the neck, planar thorax
X-ray, computer tests of pulmonary function, determination of thyroglobulin, TSH, free T4
and free T3 in serum as well as measurements of Calcium, Phosphate and differential blood
cell counts. Additionally, high resolution X-ray computed tomography (CT), wholebody
counter measurements of incorporated radionuclides and biological dosimetry have been
performed in a subset of children.
11
For treatment 50 MBq of I-131 per kg of bodyweight have been applied to eliminate thyroid
remnants. For ablation of metastases, 100 MBq of I-131 per kg of bodyweight were
administered. Simultaneously, antiemetica and emulsions for the protection of gastric
mucosa were given to reduce gastrointestinal side effects. 2 days after treatment,
replacement therapy with levothyroxine which had been withdrawn 4 weeks before treatment
was restarted. The mean dose amounted to 2.5 g of levothyroxine per kg of bodyweight;
however, suppressive therapy was individually adjusted according to serum TSH. For
staging, wholebody scans after thyroid hormone withdrawal were performed 4 days after the
application of radioiodine. The mean interval between two consecutive treatment courses
was 4.6 months.
This treatment protocol proved to be effective (see below). However, individualized “tailored”
therapeutic approaches based on prior risk certifications may be applied to childhood thyroid
cancer too. In this context, novel nuclear medicine concepts for individual dosing regimens in
radioiodine therapy may be considered [27].
Treatment response
In 234 of 247 children more than one course of radioiodine treatment has been performed in
Germany up to now. In those cases, the results of treatment could be checked by follow-up
with I-131 scintigraphy (Fig. 2), ultrasonography of the neck, planar X-ray or CT-scan of the
thorax and determinations of thyroglobulin in serum (Tab. 11).
In 131 out of 234 children (= 56%) complete remissions of thyroid cancer could be achieved
up to now (negative whole-body scans and negative thyroglobulin). In 30% we were able to
recognize stable partial remissions (negative whole-body scans and thyroglobulin < 10
ng/ml). In the remaining 14% stable partial remissions defined as decrease of tumor volume,
thyroglobulin serum level and/or intensity of radioiodine uptake for at least 50% were
observed. Fortunately, no single case showed progressive disease during the observation
period of now 13 years. It is important to mention, that the results given here are not the final
12
results of treatment since in some cases without complete remission up to now further
courses of radioiodine are applicable.
Generally, prognosis of thyroid cancer in children and adolescents is reported to be excellent
(Tab. 12). The mortality usually is low in the range of 1-2%; however, recurrence rates
typically are in the range of 30%. A systematic analysis of the course of the disease in 235
patients with differentiated thyroid cancer below age of 18 proved that total thyroidectomy
and adjuvant radioiodine treatment independently decrease the risk for local regional
recurrences [39].
Side effects of treatment
First of all, 2 studies in children from the Ukraine and Belarus show that side effects of
surgery are relatively frequent with 6-12% for hoarseness due to laryngeal nerve palsy and
hypocalcemia because of hypoparathyroidism [40,41]. Concerning radioiodine treatment in
children, a number of more or less severe side effects has to be taken into account. Those
side effects can be separated into early and late complications (Tab. 13).
Possibly, radioiodine treatment for ablation of thyroid remnants may cause radiation induced
thyroiditis (especially if the remnants are large). According to our experience, this side effect
rarely occurs in children. On the contrary, nausea and vomiting due to gastritis and/or
psychic effects has to be taken into account regularly (so that pre-treatment with effective
antiemetica is mandatory in children). A frequent side-effect in patients treated with
radioiodine for thyroid cancer – not depending on patient’s age – is sialadenitis induced by
relatively high uptake of I-131 by the salivary glands. Similarly, transient leuko- and/or
thrombopenia occurring during the first weeks after administration of radioiodine may be
seen in approximately 20% of the patients treated with radioiodine.
With respect to late side effects of combined treatment with radioiodine and TSHsuppressive doses of levothyroxine, disturbances of physical development at least
13
hypothetically may occur. However, careful follow-up by pediatric endocrinologists did not
reveal any signs of impairment of physical development in our patients. On the other hand,
this follow-up showed elevated FSH levels in 20-50% of young adolescents which have been
treated with radioiodine previously. In young males, oligo- or asthenozoospermia had to be
registered in 20-30% of the patients [51]. Sicca-syndrome as late consequence of radiation
induced sialadenitis developed in less than 10% of our group of young patients with radiation
induced thyroid cancer.
A special problem of radioiodine treatment in children is induction of pulmonary fibrosis due
to high radioiodine uptake in lung metastases with miliary spread [52]. We recognized
radiological signs of pulmonary fibrosis and/or decreased vital capacity in 8 out of 104
children with lung metastases taking up radioiodine. However, 5 of those 8 cases had been
pre-treated with Bleomycin which itself is known to induce pulmonary fibrosis. One of those
children – the very first patient who came to Germany for treatment in 1993 – unfortunately
died in 2007 of pulmonary fibrosis.
Since complete elimination of pulmonary metastases is difficult to obtain by radioiodine, the
indication for repeated I-131 therapy should be considered carefully; in a subgroup of 19 of
the 104 patients with pulmonary metastases, we observed stable partial remissions with
continuously decreasing levels of serum thyroglobulin over a period of now more than 6
years.
High dose radioiodine therapy may induce secondary tumors. This may occur after long
latency times up to 40 years. Since especially the female breast is exposed to a relatively
high radiation dose, the risk for developing breast cancer has to be taken into account
seriously. Epidemiologic studies, however, fail to prove this hypothesis [53]. The literature
review didn’t reveal a significantly increased risk of second primary malignancies after I-131
therapy in children and adolescents (Tab. 14). However, follow-up times of 10-15 years are
too short to exclude such a risk. Therefore patients treated with high activities of radioiodine,
especially children, should be carefully followed-up during their whole lifespan.
14
Tab. 1
Study
observ. expect.
cases cases
mean
dose
average excess
relat.risk at 1Gy
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)
*significant
Tab. 2
Study
observ. expect.
cases cases
mean
dose
average excess
relat.risk at 1Sv
22
110
14.9
79.4
0.27 Sv
0.26 Sv
1.80
1.49
Age at exposure
0-9 years
10-19
20-29
24
35
18
7.6
14.6
17.5
0.21 Sv
0.31 Sv
0.28 Sv
10.25*
4.50*
0.10
All
132
94.3
0.26 Sv
1.5 (95%Cl:0.5-2.1)
Sex
male
female
*significant
15
Tab. 3
Age
Men
Obs. SIR
Women
Obs. SIR
Obs.
SIR
0
7
10
3
53
32
1.09
1.51*
1.96*
3
60
42
1.01
1.57*
2.31*
Referred for Suspicion of a Thyroid Tumour (n = 11.015)
<= 20 years 0
0.00
1
1.18*
21-50 years 7
9.95*
30
2.55*
>50 years
9
17.07*
22
3.71*
1
37
31
1.14*
2.96*
4.80*
Referred for Other Reasons (n = 24.010)
<= 20 years 0
0.00
21-50 years 0
0.00
>50 years
1
0.75
2
23
11
0.96
0.89
0.94
All (n = 35.025)
<= 20 years
21-50 years
>50 years
0.00
2.27*
5.35*
2
23
10
1.05
0.98
0.97
All
Obs.=observed, SIR = Standard Incidence Ratio, *significant
16
Tab. 4
Mean thyroid dose (Gy)
Population
Evacuees of 1986, including
Size of
population
116 131
0-7 years
Adults
Total
1.82
0.29
0.48
Villages, Belarus
24 725
3.10
0.68
1.00
Pripyat town
49 360
0.97
0.07
0.17
Villages, Ukraine
28 455
2.70
0.40
0.65
Entire country
10 000 000
0.15
0.04
0.05
Gomel region
1 680 000
0.61
0.15
0.22
55 000 000
--
--
0.01
500 000
--
--
0.38
3 000 000
--
--
0.04
150 000 000
--
--
0.002
Belarus
Ukraine
Entire country
Region around Chernobyl NPP
Kiev city
Russian Federation
Entire country
Bryansk region
1 457 500
0.16
0.026
0.04
Kaluga, Orel, Tula regions
4 000 000
--
--
0.01
Tab. 5
Number of cases
Age at exposure
(years)
Belarusa
<15
15-17
Total
1711
299
2010
Russian
Federation
(4 most
contaminated
regions)b
349
134
483
Population aged
less than 15 years
2 300 000
in 1986
1 100 000
Ukrainec
Total
1762
582
2344
3822
1015
4837
11 000 000
14 400 000
17
a
Cancer Registry of Belarus, 2006.
Cancer subregistry of the Russian National Medical and Dosmetric Registry, 2006.
c
Cancer Registry of Ukraine, 2006.
b
Tab. 6
Author
Year
Patients
72
Follow-up
(months)
n.a.
PTC
(%)
n.a.
pT4
(%)
67
pN1
(%)
90
pM1
(%)
18
Schlumberger [28]
1987
Zimmermann [29]
1988
68
331
100
24
90
7
Dottorini [1997]
1997
85
111
85
31
60
19
Vassilopoulo [31]
1998
112
112
92
38
63
28
Segal [32]
1998
61
n.a.
79
26
49
6
Newman [33]
1998
329
136
90
32
74
25
LaQuaglia [34]
2000
83
131
90
48
90
100
Jarzab [35]
2000
109
60
71
n.a.
59
16
Grigsby [36]
2001
56
132
95
54
60
13
Chow [37]
2004
60
168
82
23
45
15
Popovtzer [38]
2006
75
n.a.
83
n.a.
60
6
Handkiewicz [39]
2007
235
82
82
8
40
17
Rybakov [40]
2000
330
180
94
55
62
15
Demidchik [41]
2006
741
97
95
16
69
18
after Chernobyl
18
Tab. 7
Nodules and Features
B Coefficient*
T-Value
P-value
All
Nodule size
0.03 ± 0.01
3.63
<.001
Hypoechogenicity
0.17 ± 0.07
2.55
<.05
Outline irregularity
0.30 ± 0.07
3.93
<.001
Subcapsular location
0.33 ± 0.08
3.87
<.001
Type III vascularization
0.13 ± 0.04
3.34
<.01
Nodule size
0.03 ± 0.02
2.09
< .05
Hypoechogenicity
0.07 ± 0.07
1.080
.28
Outline irregularity
0.35 ± 0.08
4.22
< .001
Subcapsular location
0.30 ± 0.08
3.48
< .001
Type III vascularization
0.14 ± 0.04
3.27
< .01
Nodule size
0.03 ± 0.02
1.06
.30
Hypoechogenicity
0.49 ± 0.15
3.27
<.01
Diameter ≤ 15 mm
Diameter > 15 mm
*Values expressed as mean ± standard error
]
19
Tab. 8
Item
Tumor size (mm)
Microcarcinomas (≤ 10 mm)
Large tumors (> 40 mm)
Entire series
Radiogenic
Sporadic
14.9 ± 8.5a
14.9 ± 8.6
15.0 ± 8.3
278 (37.0)b
260 (37.9)
18 (27.3)
1.1086
7 (1.0)
1 (1.5)
0.5222
0.7432
8 (1.1)
p-value
Type of malignancy
Solitary
608 (80.9)
553 (80.6)
55 (83.3)
Multifocal
144 (19.1)
133 (19.4)
11 (16.7)
T1
548 (72.9)
498 (72.6)
50 (75.8)
0.6647
T2
78 (10.5)
72 (10.5)
6 (9.1)
0.8352
T3
122 (16.2)
113 (16.5)
9 (13.6)
0.7262
T4
2 (0.3)
2 (0.3)
0
1.0000
TX
2 (0.3)
1 (0.2)
1 (1.5)
0.1679
N1
523 (69.6)
477 (69.5)
46 (69.7)
1.0000
M1
17 (2.3)
16 (2.3)
1 (1.5)
1.0000
pTNM distribution
Clinical manifestations
Asymptomatic
574 (76.3)
518 (75.5)
56 (84.8)
0.0964
With symptoms
163 (21.7)
156 (22.7)
7 (10.6)
0.0193
12 (1.8)
3 (4.5)
0.1372
Unknown
15 (2.0)
a
Mean ± standard deviation
Number of subjects (percentage)
b
20
Tab. 9
Patterns of failure
Radiogenic
Sporadic
p-value
89 (11.8)a
86 (12.5)
3 (4.5)
0.0697
59 /7.8)
58 (8.5)
1 (1.5)
0.0514
Relapse in thyroid remnants
3 (0.4)
3 (0.4)
0
1.0000
Soft tissue metastases
1 (0.1)
1 (0.2)
0
1.0000
Lymph nodes and thyroid remnants
10 (1.3)
9 (1.3)
1 (1.5)
0.6032
Neck lymph nodes and lung metastases
26 (3.5)
26 (3.8)
0
0.1569
Lymph nodes and soft tissue metastases
2 (0.3)
2 (0.3)
0
1.0000
Lymph nodes, lung and bone metastases
1 (0.1)
1 (0.2)
0
1.0000
Lymph nodes, lung and CNS metastases
1 (0.1)
1 (0.2)
0
1.0000
Lymph nodes, lunge, bone and CNS
1 (0.1)
1 (0.2)
0
1.0000
Lymph nodes, lung and thyroid remnants
5 (0.7)
4 (0.6)
1 (1.5)
0.3691
Lunge, bone and soft tissue metastases
1 (0.13)
1 (0.15)
0
1.0000
Lung and soft tissue metastases
2 (0.27)
1 (0.15)
1 (1.5)
0.1679
Lung metastases and thyroid remnants
3 (0.40)
3 (0.44)
0
1.0000
197 (28.7)
7 (10.6)
0.0012
Lung metastases (M1 cases included)
Positive neck lymph nodes
Total
Total
204 (27.1)
a
Number of subjects (percentage)
21
Tab. 10
Patients
247 Children
1053 Treatment Courses
Origin
100 Gomel Area
147 Other Parts of Belarus
Gender
147 Girls
100 Boys
Age
7 - 23 Years (13.4 ± 3.1)
Histology
245 Papillary Cancers
2 Follicular Cancers
Stage
pTx -
2
pN0 -
8
pM0 - 143
pT1 -
7
pN1- 237
pM1 - 104
pT2 - 81
pT3 -
pNX
2
4
104 Lung
+ 2 Bone, 1 Brain
pT4 – 153
Pretreatment
39 Radioiodine Therapies in Minsk
5 Radioiodine Therapies in Italy
19 Percutaneous Irradiations
6 Chemotherapies
22
Tab. 11
Complete
Remission
Stable Partial
Remission
Partial
Remission
M0
1
--
--
M1
1
1
2
M0
53
10
--
M1
M0
4
--
2
1
18
--
M1
--
2
--
M0
41
24
1
M1
31
30
19
N=234
N0
pT1-3
N1
N0
pT4
N1
Tab. 12
Author
Year
Total
LN-
I-131
LT4
Hoarse-
Hypo-
Res.
Dis-
Ther.
Med.
ness
Calcem.
Mortality
Recurrence
section
Schlumberger [28]
1987
40%
n.a.
22%
n.a.
11%
7%
n.a.
58%
Zimmermann [29]
1988
76%
60%
20%
Most.
0%
24%
15%
48%
Dottorini [30]
1997
56%
n.a.
89%
Most.
4%
8%
0%
7%
Vassilopoulo [31]
1998
72%
62%
Most.
Most.
n.a.
n.a.
29%
40%
Segal [32]
1998
83%
59%
100%
100%
10%
10%
3%
33%
Newman [33]
1998
54%
56%
43%
n.a.
2%
12%
1%
33%
LaQuaglia [34]
2000
66%
51%
100%
100%
1%
12%
0%
31%
Jarzab [35]
2000
100%
100%
100%
100%
10%
6%
0%
15%
Grigsby [36]
2002
92%
95%
82%
100%
0%
7%
0%
34%
Chow [37]
2004
82%
87%
60%
100%
n.a.
n.a.
3%
22%
Popovtzer [38]
2006
89%
100%.
89%
100%
12%
5%
3%
9%
Handkiewicz [39]
2007
73%
67%
74%
100%
n.a.
n.a.
0%
14%
23
Rybakov [40]
2000
84%
57%
75%
100%
12%
6%
2%
7%
Demidchik [41]
2006
58%
82%
63%
100%
6%
12%
1%
28%
after Chernobyl
Tab. 13
Early side effects
Late side effects
Radiation Thyroiditis
Rare
Disturbances of Physical
Development
n.s.
Gastritis (Nausea, Vomiting)
50-80%
Impairment of Gonadal
Function
20-50%
Sialadenitis
20-30%
Oligo-/Asthenozoospermia
20-30%
Leuko-/Thrombopenia
20%
Sicca-Syndrome
<10%
Pulmonary Fibrosis (M+)
5%
Leukemia
1-2%(?)
(Reversible)
24
Tab. 14
Authors
Number of subjects
of I-131 treated
Dottorini et al.
Rubino et al.
59
344*
Age Range at
Diagnosis
Mean Follow-Up
Period
Second primary
tumors
< 18 y.o.
111 months (1-
2 cases (Breast,
324 months)
Stomach)
Not described
13 cases (Both
< 20 y.o.
Adult and
Childhood)**
Chow et al.
36
< 21 y.o.
14 years
Not described
Hod et al.
31
< 25 y.o.
60 months (16-
Not described
29
Shapiro et al.
Collini et al.
150 months)
1***
< 18 y.o.
-155 months
Not described
13
< 17 y.o.
189 months (39-
Not described
368 months)
Demidchik et al.
464
< 15 y.o.
Drozd et al.
228
< 12 y.o.
115.8
months(1.5236.4 months)
10 years
Not described
2 cases
(Salivary gland,
Syringoepithelioma)
*Both of external radiotherapy and I-131 therapy
**There was no significant association between the risk of second primary malignancy and I-131 therapy
***The number of subjects was described as 51.4% of 566 cases
25
Legends:
Fig. 1: Thyroid cancer incidence in children and adolescents from Belarus after the
Chernobyl accident [14]
Fig. 2: Post-therapeutic I-131 wholebody scans in the course of effective radioiodine
treatment in a 13 year old boy with papillary thyroid cancer pT4 N1b M1
Tab. 1: Thyroid cancer after exposure to irradiation: Cohort and Screening Studies of
Children [3]
Tab. 2: Thyroid cancer after exposure to irradiation: The Life Span Study from Japanese ABomb Survivors [6]
Tab. 3: Thyroid cancer after internal exposure: The Swedish I-131 Diagnosis (1952-1969)
Follow-Up Study (1998) in 36.792 Patients
Tab. 4: Estimates of thyroid doses in children and adults after Chernobyl [10,11,12,13]
according to Cardis et al. [14]
Tab.5 Number of cases of thyroid cancer diagnosed after Chernobyl between 1986 and
2002, by country and age at exposure [14]
Tab 6: Thyroid cancer in children and adolescents (studies with more than 50 patients):
Pathological findings
Tab. 7: Characteristics of thyroid cancer in Chernobyl children with small (≤ 15 mm) and
larger (> 15 mm) nodules [47
Tab. 8: Pathological staging and clinical manifestations of thyroid cancer in children of
Belarus [48]
Tab. 9: Sites of recurrences and numbers of thyroid cancer in children of Belarus [48]
Tab.10: Children with advanced differentiated thyroid cancer from Belarus treated with I-131
in Germany between 1993 and 2007
Tab. 11: Results of radioiodine treatment in 234 children with advanced differentiated thyroid
cancer from Belarus (01/04/1993 – 31/12/2007)
Tab. 12: Thyroid cancer in children and adolescents (studies with more than 50 patients)
Tab.13: Early and late side effects of radioiodine therapy in children with differentiated
thyroid cancer
Tab. 14: Risk of secondary malignancies in young patients treated with radioiodine for
differentiated thyroid cancer [53]
26
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31