Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant

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1 Endocrine Journal 2014, 61 (9), Original Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant Kenji Iwaku, Jaeduk Yoshimura Noh, Eiji Sasaki, Nami Suzuki, Tosiaki Kameda, Sakiko Kobayashi, Ai Yoshihara, Hidemi Ohye, Natsuko Watanabe, Miho Suzuki, Masako Matsumoto, Yo Kunii, Koji Mukasa, Kiminori Sugino and Koichi Ito Ito Hospital, Tokyo , Japan Abstract. Following the accident at the Fukushima Daiichi Nuclear Power Station which occurred on March 11, 2011 due to the Eastern Japan Great Earthquake (the Accident), there have been concerns over elevation of the risk of thyroid cancer among children due to internal exposure to radioactive iodine. In Fukushima Prefecture, screening of children with thyroid ultrasonography has been carried out, yielding numerous findings, suggesting a possible influence from the Accident. We report thyroid ultrasonographic findings, used by similar device at Fukushima Prefecture s study, at Ito-hospital. Of the 2721 children aged 15 or less who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age, 12; range of age, 4-15) were covered by evaluation of thyroid ultrasonographic findings, excluding children known in advance to have thyroid disease on the basis of disease history, palpation and blood tests. Among these 1214 children, 709 children (58.4%) were found cysts ( 5 mm in 665 cases) by ultrasonography, 43 children (3.5%) were found nodules ( 5 mm in 18 cases) and 9 children (5.2%) were found an intrathyroid ectopic thymus. Analysis of the data before and after the Accident using the same device, involving age adjustment on the basis of the standard population in 2010, showed no difference in the incidence rate of cysts or nodules. In children examined, the incidence rate of cyst formation (particularly 5 mm) was higher, and there was no difference in the incidence rate of cysts or nodules between the pre- and post-accident period. Key words: Thyroid sonograms, Pediatric, Thyroid IN CLINICAL PRACTICE, it is not uncommon for minor thyroid lesions to be incidentally detected by thyroid ultrasonography in subjects with no evident abnormality detected by palpitation of the thyroid gland. Thyroid ultrasonography plays a well-recognized and important role in routine clinical practice [1-3]. After the accident at the Fukushima Daiichi Nuclear Power station (hereinafter called the Nuclear Power Station Accident ) which occurred on March 11, 2011, after the Great East Japan Earthquake, there have been concerns about a possible increase in the incidence of thyroid cancer in children due to internal exposure to radioactive iodine, as previously seen in Belarus following the accident at Chernobyl [4-8]. Submitted Jan. 21, 2014; Accepted Jun. 8, 2014 as EJ Released online in J-STAGE as advance publication Jul. 8, 2014 Correspondence to: Kenji Iwaku, M.D., Ph.D., Ito Hospital, Jingumae, Shibuya-ku, Tokyo , Japan k-iwaku@ito-hospital.jp The Japan Endocrine Society Under these circumstances, a thorough screening by thyroid ultrasonography, covering all the children living in Fukushima Prefecture at the time, was carried out at the initiative of the Fukushima Medical University [9]. According to an, interim report (as of September 30, 2013), abnormalities were detected in (46.7%) of the children examined [10]. In the only such study carried out in Japan before the Nuclear Power Station Accident, cysts were detected in 2 (0.8%) of 250 children examined by thyroid ultrasonography, and there were no cases of nodule detection [11]. Thus, there is a seemingly large discrepancy in the results between the evaluation prior to the accident and that after the accident. Because the data available from Fukushima Prefecture do not include control data, i.e., the thyroid ultrasonography data of children of the same region before the accident, it is difficult to judge the influence of the Nuclear Power Station Accident on the results obtained after the accident. At

2 876 Iwaku et al. our hospital, which covers prefectures of the Kanto District adjacent to Fukushima Prefecture as the medical treatment zone, ultrasound devices equivalent to or more advanced than the device currently in use in the thyroid ultrasonographic screening program for children in Fukushima Prefecture have been used in routine clinical practice since 2005, that is, for over 8 years now. Therefore, we analyzed the thyroid ultrasonographic findings in children at our hospital during the past 8 years with reference to the available clinical information. Herein, we report our findings. Subjects and Methods Subjects Of the 2721 children aged 15 years or lower who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age: 12 years; age range: 4-15 years) living in prefectures within or adjacent to the Kanto District (Tokyo, Kanagawa, Saitama, Chiba, Ibaraki, Tochigi, Gunma, Yamanashi, Shizuoka and Nagano), as illustrated in Fig. 1, were covered by this analysis. Children known in advance to have thyroid disease on the basis of the disease history, findings on palpation and/or the results of blood tests were excluded from the study. In these 1214 children, thyroid ultrasonography was performed and the percentage of cases with abnormal findings was analyzed. Methods Devices used In accordance with the Study Protocol for the Fukushima Health Management Survey, ultrasonography was carried out with the following devices fitted with 10-MHz or higher-frequency digital linear probes [9] : 10-MHz digital probe (LOGIQ E9, Voluson E8 [GE Healthcare, Japan], HDI 5000 [Philips, Japan]) 2010 and thereafter: 12-MHz digital linear probe (SSA-680A [Toshiba, Japan]) Examiner Ultrasonography was performed by staff members certified by the Japan Society of Ultrasonics in Medicine specializing in body sonography (JSUM Registered Medical Sonographers) and the laboratory technicians were supervised by these specialists. Evaluation of the ultrasonographic findings The results of the thyroid ultrasonography were classified as follows: (1) absence of nodules and cysts; Fig. 1 Selection of the subjects We excluded patients in the order of the criteria listed below from the total number of patients who came to our hospital, and extracted the patients with no abnormal findings other than the ultrasonography findings as the subjects of our study. Order of application of the exclusion criteria: Visitors from prefectures distant from Kanto District, patients diagnosed as having thyroid disease before visit to our hospital, patients referred to our facility because of abnormal thyroid function or thyroid node, patients having palpable diffuse goiter or thyroid nodes, patients who did not undergo a blood test at our hospital, and Patients with autoimmune thyroid disease, etc., diagnosed with a blood test. (2) presence of cysts; (3) presence of nodules; (4) presence of an intrathyroid ectopic thymus. In cases with multiple cysts or nodules, the cysts/ nodules were classified according to the diameter of the largest lesion ( 5 mm or > 5 mm). A node with solid components found in a cyst was classified as a nodule. An intrathyroid ectopic thymus was defined as an intrathyroidal lesion showing hypoechogenicity with multiple linear echogenic branching structures or punctate echogenic foci, as proposed by Kim HG et al. [12]. Blood test Thyroid function was evaluated on the basis of the ECLusys FT3, FT4 and TSH levels (Roche Diagnostics GmbH, Mannheim, Germany) in comparison with the available reference data for corresponding age groups

3 Pediatric thyroid sonograms in Japan 877 [13]. TgAb and TPOAb were measured by a radioimmunoassay (RIA) technique between January 2005 and May 2006 (TgAb Cosmic II and TPOAb Cosmic II; Cosmic Co., Tokyo, Japan), with the criterion range set at 2.6 U/mL for TgAb and at 6.7 U/mL for TPOAb. After May 2006, these parameters were measured by electrochemiluminescence immunoassay (ECLIA) (Roche ECLusys Anti-Tg and Anti-TPO; Roche Diagnostics GmbH, Mannheim, Germany), with the criterion range set at 40 IU/mL for TgAb and at 28 IU/mL for TPOAb. Statistical analysis Because the distribution of the age and gender in the population surveyed in this study differed from that of the standard population in Japan, the data were adjusted for age on the basis of the standard population data for the population aged 4-15 years derived from the National Census in 2010 [14]. The statistical analysis was conducted using JMP, version 8.02 (SAS Institute Inc., Cary, NC). The influence of age on the incidence rates of cysts, nodules and intrathyroidal ectopic thymus was evaluated by logistic regression analysis. Analysis of the incidence rates of cysts, nodules and intrathyroidal ectopic thymus before and after the Nuclear Power Station Accident in relation to the frequency of the ultrasonic probe used and gender was carried out by the chisquare after adjustment for age. This study was performed in compliance with the Declaration of Helsinki: written informed consent was obtained from the parents or guardian of each child and adequate measures were taken to prevent identification of individual children during the analysis. Results 1) Reason for hospital visit Table 1 lists the reasons for the visit to our hospital of individual children. 2) Incidence of abnormal ultrasonographic findings among all the subjects Table 2 shows the data on the numbers of cysts, nodules and intrathyroid ectopic thymus detected by ultrasonography among the children surveyed. Cysts were detected in 709 children (58.4%), ranging in diameter from 1.4 mm to 9.9 mm; 93.8% of all cysts were 5 mm in diameter, and most of the children had multiple cysts. Nodules were detected in 43 children (3.5%), ranging in diameter from 1.5 mm to 14.6 mm; 41.9% of all nodules were 5 mm in diameter. The largest nodule (14.6 mm in diameter) was a flat nodule ( mm) located on the dorsal side of the thyroid. 3) Findings classified by the probe frequency Table 3 shows the incidence rates of cysts and nodules in accordance with the frequency of the ultrasonographic digital linear probe used, after adjustment of the data for the age of the children using the 2010 National Census age-wise population data, because of the differences in the age distribution among the roups compared in this study. The incidence rate of cysts (particularly cysts 5 mm in diameter) was significantly higher among the children examined using the 12-MHz probe than among those examined using the 10-MHz probe (p = 0.032, χ 2 test); on the other hand, there were no significant differences in the overall incidence rate of cysts, incidence rate of cysts > 5 mm in diameter, or incidence rate of nodules ( 5 mm or >5 mm) depending on the probe frequency. 4) Evaluation with the 12-MHz digital linear probe Table 4 shows the effect of age on the incidence rates of cysts, nodules and intrathyroidal ectopic thymus among children who underwent ultrasonography with a 12-MHz digital linear probe. The incidence rate of cysts rose significantly with age for each category of cysts (all cysts, cysts with a maximum diameter of 5 mm, and cysts with a maximum diameter of >5 mm). The incidence rate of nodules did not differ depending on the age for any category of nodules (all nodules, nodules with a maximum diameter of 5 mm, nodules with a maximum diameter of > 5 mm). The incidence rate of intrathyroidal ectopic thymus rose significantly with age. Table 5 shows the differences in the incidence rates of cysts and nodules between males and females who underwent ultrasonography with a 12-MHz digital linear probe. This analysis was carried out after adjustment for age on the basis of the 2010 National Census age-wise population data, because of the differences in the age distribution between the groups compared. Neither the incidence rate of cysts nor that of nodules differed significantly between the males and females. Table 6 shows the differences in the incidence rates of cysts and nodules after the Nuclear Power Station Accident as compared with those before the accident in the groups who underwent ultrasonography

4 878 Iwaku et al. Table 1 Reasons for the subjects of this study to visit our facility the nuclear power accident total pre post point out of neck swelling by a medical checkup or previous clinic 438(36.1%) 270(39.6%) 168(31.6%) awareness of neck swelling 66(5.44%) 40(5.9%) 26(4.9%) symptoms associated with thyroid dysfunction 298(24.5%) 180(26.4%) 118(22.2%) concern about thyroid disease 412(33.9%) 192(28.2%) 220(41.3%) anxiety concerning a positive family history concern as a result of information gained from mass media or acquaintances apprehensions relevant to the nuclear power accident total Table 2 Number of cases with cysts, nodules and intrathyroidal ectopic thymus, incidence rate and influence of age in the total population studied Age group total Cases 4-5y.o 6-10y.o 11-15y.o OR[95%CI] p Cyst All 24(34.3%) 176(51.3%) 509(63.5%) 709(58.4%) 1.12(1.08,1.16) < Cyst( 5mm) 24(34.3%) 170(49.6%) 471(58.8%) 665(54.8%) 1.10(1.06,1.14) < Cyst(>5mm) 0 6(1.7%) 38(4.7%) 44(3.6%) 1.20(1.06,1.37) Nodule All 0 15(4.4%) 28(3.5%) 43(3.5%) 0.99(0.90,1.23) Nodule( 5mm) 0 6(1.7%) 12(1.5%) 18(1.5%) 1.04(0.89,1.23) Nodule(>5mm) 0 9(2.6%) 16(2.0%) 25(2.1%) 0.96(0.85,1.09) Intrathyroid ectopic thymus 2(2.9%) 6(1.7%) 1(0.1%) 9(4.2%) 0.69(0.54,0.85) OR indicates odds ratio per 1 year. CI indicates confidence interval Table 3 Incidence rate of cyst and nodule in relation to the frequency of the ultrasonography digital linear probe used 10MHz 12MHz p(χ 2 test) Cyst 46.47(%) 59.50(%) Cyst( 5mm) 42.47(%) 57.63(%) Cyst(>5mm) 3.99(%) 1.47(%) Nodule 3.10(%) 1.48(%) Nodule( 5mm) 1.83(%) 0.69(%) Nodule(>5mm) 1.27(%) 0.79(%) The data were adjusted for age on the basis of the standard population data from the National Census in 2010 Table 4 Number of cases with cysts, nodules and intrathyroidal ectopic thymus, their incidence rate and influence of age among the subjects examined with a 12 MHz digital linear probe Age group total 4-5y.o 6-10y.o 11-15y.o OR[95%CI] p Cases Cyst 23(34.3%) 117(56.0%) 316(71.8%) 456(63.7%) 1.16(1.11,1.22) < Cyst( 5mm) 23(34.3%) 115(55.0%) 301(68.4%) 439(61.3%) 1.14(1.09,1.19) < Cyst(>5mm) 0 2(1.0%) 15(3.4%) 17(2.4%) 1.23(1.03,1.52) Nodule 0 10(4.8%) 15(3.4%) 25(3.5%) 0.99(0.88,1.11) Nodule( 5mm) 0 2(1.0%) 7(1.6%) 9(1.3%) 1.11(0.90,1.43) Nodule(>5mm) 0 8(3.8%) 8(1.8%) 16(2.2%) 0.93(0.81,1.08) Intrathyroid ectopic thymus 1(1.5%) 5(2.4%) 1(0.2%) 7(1.0%) 0.76(0.59,0.95) OR indicates odds ratio per 1 year. CI indicates confidence interval.

5 Pediatric thyroid sonograms in Japan 879 Table 5 Incidence rate of cyst and nodule analyzed by gender among the subjects examined with a 12 MHz digital linear probe Male Female p(χ 2 test) Cyst 51.86(%) 64.38(%) Cyst( 5mm) 51.34(%) 62.33(%) Cyst(>5mm) 1.00(%) 2.04(%) Nodule 4.05(%) 3.21(%) Nodule( 5mm 0.49(%) 1.38(%) Nodule(>5mm) 3.56(%) 1.51(%) The data were adjusted for age on the basis of the standard population data from the National Census in 2010 Table 6 Incidence rate of cysts and nodules before and after the Nuclear Power Station Accident among subjects examined with a 12 MHz digital linear probe Pre Post p(χ 2 test) Cyst 60.32(%) 59.1(%) Cyst( 5mm) 59.00(%) 57.04(%) Cyst(>5mm) 1.32(%) 2.06(%) Nodule 3.31(%) 3.48(%) Nodule( 5mm) 1.32(%) 0.94(%) Nodule(>5mm) 1.99(%) 2.54(%) The data were adjusted for age on the basis of the standard population data from the National Census in 2010 with a 12-MHz digital linear probe. This analysis was also carried out after adjustment for age on the basis of the 2010 National Census data because of the differences in the age distribution among the groups compared. No significant differences were noted in the incidence rates of cysts or nodules before and after the accident in this analysis. Discussion There has been concern over a possible elevation in the number of children with thyroid cancer due to internal exposure to radioactive iodine after the Nuclear Power Station Accident of March 11, 2011 [4-8]. In Fukushima Prefecture, where the accident took place, the Fukushima Health Management Survey Program [9] was initiated, and children throughout the prefecture were screened for thyroid lesions by thyroid ultrasonography. According to an interim report, as of August 23, 2013, abnormalities were detected in (46.7%) of the children examined [10]. Thus, abnormal findings were obtained in a rather high percentage of children as compared to that in a previous report from Japan, according to which cysts were found in only 2 (0.8%) of 250 children examined [11]. However, the ultrasound devices used in the previous study were less advanced (fitted with a 7.5-MHz digital linear probe) and it is difficult to compare the results of that study directly with the results of the recent thyroid ultrasonographic screening examinations carried out in Fukushima. Under these circumstances, with the results being so discrepant, we undertook the present study to collect reliable data about the rate of abnormal thyroid ultrasonographic findings among children in Japan. When performing this study, we attached primary importance to the selection of a study population closest to the general population. Our hospital specializes in the care of thyroid diseases, and all of the subjects of this study visited out hospital, seeking outpatient thyroid care. Thus, an accurate diagnosis was based on the condition of the thyroid of each subject, through a detailed check of the reason for the visit, detailed interview, general check-up by a clinician (inspection/palpation) and blood tests (performed for all visitors unless there was any special reason to skip it). Among these patients in whom a thyroid condition was definitively diagnosed, those satisfying the following requirements were selected for this study: (1) no goiter or thyroid node detectable by thyroid gland palpation; (2) euthyroid status and negative results of blood tests for anti-thyroid antibodies; so normal thyroid subject withyout thyroid ultrasonographic findings. Furthermore, as also reported previously by Guth S et al. [15] we found that the capability of ultrasonography to detect small cysts ( 5 mm) differed depending on the frequency of the digital linear probe used for the examination, whereas no clinically significant difference in the detection capability depending on the probe frequency was noted for cysts, nodules or other lesions > 5 mm in diameter. Based on this finding, we confined our pre-accident/post-accident comparison of the rate of abnormal ultrasonographic findings to patients who underwent ultrasonography with the same device under identical settings. In this analysis conducted at our facility, cysts and nodules were detected in a rather high percentage of the subjects (61.9%, 752/1214 subjects) who had shown no abnormalities before the ultrasonography, i.e. who were found to have no goiter or thyroid nodules on palpation of the thyroid gland, were euthyroid,

6 880 Iwaku et al. and showed negative results of the blood tests for antithyroid antibodies. Cysts were detected in 709 subjects (58.4%), with the cysts measuring 5 mm in 93.8% (665/709) of the cases. Nodules were detected in 43 subjects (3.5%), with nodules measuring >5 mm being slightly predominant (58.1%, 25/43 cases). All of the thyroid nodules detected 20 mm in diameter. In accordance with the treatment recommended by the Japan Association of Breast and Thyroid Sonology [16], we performed puncture and aspiration for cytodiagnosis in one case with suspected malignancy (irregular, ill-defined jagged, low, heterogeneous, etc.) on the basis of the Ultrasound Diagnostic Criteria for Thyroid Nodules established by the Japan Society of Ultrasonics in Medicine [17]; however, the cytodiagnosis revealed no sign of malignancy. Concerning comparison of the results in this study with the data reported from other districts, the survey of Fukushima Prefecture inhabitants conducted by the Fukushima Prefectural Government revealed cysts in individuals (45.5%) among the individuals surveyed, the cysts measuring 5 mm in diameter in of the individuals (99.99% cases) (data as of August 23, 2013 published on the prefecture s homepage) [10]. According to the report by Hayashida N et al., who published combined data from 3 districts (Hirosaki City Aomori Prefecture, Kofu City Yamanashi Prefecture and Nagasaki City Nagasaki Prefecture), cysts were detected in 2483 (56.9%) of 4365 individuals, the cysts measuring 5 mm in diameter in 2283 of the individuals (91.9%) [18]. In all of these surveys, the incidence rate of cysts was high and cysts 5 mm in diameter accounted for the overwhelming majority of the cases, similar to the tendency observed at our facility. According to the Fukushima Prefecture Government s report, nodules were detected in 2710 (1.2%) of individuals, including nodules > 5 mm in diameter in 1541 individuals (56.9%) [10]. According to the report of Hayashida N et al., nodules were detected in 72 (1.65%) of 4365 individuals, including nodules > 5 mm in diameter in 44 individuals (61.1%) [18]. In the international literature, Avulas et al. performed thyroid ultrasonography on 287 individuals (mean age 8.1) visiting their facility in Toronto (Canada) with chief complaints not related to the thyroid, and reported that cysts (< 4 mm in diameter) were detected in 35 individuals (12.2%) and smoothly demarcated hypoechoic nodules and an intrathyroid ectopic thymus were seen in 9 individuals (3.1%) [19]. Thus, while the incidence rate of nodules differs among reports, nodules > 5 mm in diameter were slightly predominant in all reports. Factors possibly involved in the differences in the incidence rates among different reports include regional differences in the age distribution or iodine intake, family history, differences in the ultrasonographic devices used, differences in the examiners, etc., although no definitive reason has been identified yet. An intrathyroidal ectopic thymus was detected in 9 individuals (4.2%), and its incidence rate decreased with age, similar to the tendency reported by Hayashida N et al. [18]. Regarding the development of the thymus, it is known that the epithelium of the third pharyngeal pouch grows to close the inner medulla, then the bilateral primordia of the thymus fuse with each other on the median plane, forming the thymus. Thereafter, the thymus descends into the superior mediastinum via the neck, along the dorsal plane of the thyroid. If the thymus partially remains in the thyroid during this process, an intrathyroidal ectopic thymus is formed. According to one report, among 9 patients with an intrathyroid ectopic thymus (mean age, 6.3) who underwent longterm follow-ups, the ectopic thymus grew smaller over time [20], thus endorsing the findings of our study. When the incidence rate of nodules was compared between the pre- and post-accident data, the rate at 2 years after the accident did not differ from the preaccident rate in the present study. The reports made after the accident at the Chernobyl Nuclear Power Station in 1986 did not refer to the incidence rate of nodes in Belarus or Ukraine, only referring to the rate of thyroid cancer among children [4-8]. In those reports, the rate of thyroid cancer rose sharply from the 4th year onward after the accident, without showing any increase until the 4th year, identical to the results of the present study. Disclosure Statement None of the authors have any potential conflicts of interest associated with this research. The authors declare that they have no competing financial interests.

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