Findings of Thyroid Ultrasound Examination Within 3 Years After the Fukushima Nuclear Power Plant Accident: The Fukushima Health Management Survey

Findings of Thyroid Ultrasound Examination Within 3 Years After the Fukushima Nuclear Power Plant... Abstract Context Childhood thyroid cancer is of great concern after the Fukushima nuclear power plant accident. Baseline analytical data on thyroid ultrasound examination (TUE) in children are important for future studies. Objective We analyzed the age and sex distribution of findings from the TUEs of children and adolescents in the Fukushima Health Management Survey (FHMS). Design, Setting, and Participants From October 2011 through March 2014, 294,905 participants aged 18 years or younger at the time of the earthquake voluntarily had TUEs in the first round of the FHMS. A secondary confirmatory examination was performed in 2032 subjects. Age- and sex-dependent prevalence and size of thyroid cysts, nodules, and cancers were analyzed. Main Outcome Measures Age, sex, and size distribution of findings were analyzed. Results Thyroid cysts, nodules, and cytologically suspected cancers were detected in 68,009, 1415, and 38 male subjects and in 73,014, 2455, and 74 female subjects, respectively. There was an age-dependent increase in the detection rate of thyroid nodules and cancer, but that of cysts reached a peak at 11 to 12 years. Sex affected the prevalence of thyroid nodules and cancers after the onset of puberty, but only a small difference was exhibited in that of cysts. Conclusions The thyroid cancer detection rate in Fukushima was clarified, and the proportion of individuals with thyroid nodules and cysts varied substantially by age. The results of this study will contribute to future epidemiological research on nodular thyroid diseases in children and adolescents. Childhood thyroid cancer is of great concern in Fukushima Prefecture, and the fear of cancer is prominent throughout Japan because previous studies have reported that one of the main adverse health effects of radiation fallout from nuclear power plant accidents, especially the Chernobyl nuclear power plant accident, has been a substantial rise in thyroid cancer among exposed young people (1–3). Because radiation exposure levels in Fukushima residents were considered to be much lower than those in Chernobyl residents, a large increase in thyroid cancer rates due to radiation exposure, such as that which occurred after the Chernobyl accident, had not been expected (4). However, it was necessary to conduct surveys for both scientific and social demands (5). The Fukushima prefectural government started to examine thyroid glands by using ultrasound examination and common standardized diagnostic criteria among residents aged 18 years or younger from 7 months after the Fukushima Daiichi nuclear power plant accident (5–7) The first-round survey, during the first 3 years after the accident, is evaluated as baseline data prior to the period in which radiation effects on the thyroid gland could potentially occur (5). Because there have been no data on the thyroid ultrasound examination (TUE) among asymptomatic children and adolescents in a population of this size (i.e., hundreds of thousands) (8), it is worthwhile to share some of the findings from the survey. The same examination and diagnostic methods were used in a study of 3- to 18-year-old children performed in three prefectures located far from Fukushima (Aomori, Yamanashi, and Nagasaki), for a total sample size of 4365 (9–11). We report herein the precise age and sex differences in the findings from the TUEs performed on children and adolescents, which was conducted in the first-round examination of the Fukushima Health Management Survey (FHMS). The results demonstrated in this study will serve as reference data for future epidemiological studies of nodular thyroid diseases in children, adolescents, and young adults. Materials and Methods Study population Subjects were inhabitants of Fukushima Prefecture aged between 0 and 18 years on 1 April 2011. The preliminary baseline survey, the first-round of TUE, was conducted from October 2011 through March 2014 as part of the FHMS and was extended to April 2015 to provide an opportunity for nonparticipants to have this examination (5, 7). Among the target population of 367,672, 300,476 subjects (81.7%), including evacuees currently living in other prefectures, voluntarily participated in this survey (12, 13). This study included 294,905 participants who had TUE from October 2011 to March 2014. These subjects were 0 to 18 years of age at the time of the earthquake and 0 to 21 years of age at the time of examination. This survey was approved by the ethics review committee of Fukushima Medical University (no. 1318). Written informed consent was obtained from the parents or guardians of all surveyed children. The raw data used to create all tables in the current study are unavailable due to a restriction outlined in the informed consent. Primary TUE Ultrasound was used to examine the thyroid gland. A detailed protocol has been reported elsewhere (6, 7, 14). In brief, ultrasound examination was conducted using a LOGIQ e Expert (GE Health Care, Tokyo, Japan) with a 12L-RS linear probe (10–12 MHz) and a Noblus (Hitachi-Aloka, Tokyo, Japan) with a 12 MHz linear probe. This highly sophisticated method detects nodules and cysts <1 mm in size and records thyroid volume and other findings, such as congenital defects and ectopic thymus. In subjects with nodules, the examiner recorded the multifocality of nodules and the location of the largest nodule and measured the greatest dimension of the largest nodule. In subjects with cysts, the assessor also recorded the multifocality of the cysts and the location of the largest cyst and measured the greatest dimension of the cysts. In our survey, the mixed solid-cystic type tumor, which is a cyst with a solid component, was not classified as a cyst; it was classified as a nodule because this mixed-type tumor sometimes occurs in thyroid cancer (7). Secondary confirmatory TUE Subjects with nodules ≥5.1 mm or cysts ≥20.1 mm were recommended to undergo a secondary confirmatory examination. Physicians credentialed by the Japan Thyroid Association, Japanese Society of Thyroid Surgery, Japan Society of Ultrasonics in Medicine performed the confirmatory examination using the highest-resolution instrumentation. This confirmatory examination included a precise ultrasound examination, blood and urine tests, and fine-needle aspiration cytology (FNAC) if sonographic findings of nodules or cysts met the FNAC criteria according to the guidelines issued by the Japan Association of Breast and Thyroid Sonology (12, 14). According to guidelines of the Japan Association of Breast and Thyroid Sonology, FNAC is recommended for nodules >5 mm in diameter that are strongly suspicious for thyroid carcinoma using Japan Society of Ultrasonics in Medicine diagnostic criteria (14), nodules >10 mm in diameter and suspicious for carcinoma using the above criteria, nodules >20 mm in diameter, and cystic lesions >20 mm in diameter. These guidelines were followed to avoid unnecessary FNAC, especially for nodules >5 mm but <10 mm. If a benign lesion was detected by ultrasonography only or by ultrasonography and FNAC, the subjects were recommended to undergo a follow-up treatment under Japan’s comprehensive medical coverage program. If a malignancy was suspected or detected by FNAC, the subject would require surgical treatment. Statistical analysis All results shown in this study were analyzed using the subject’s age at time of the primary examination instead of their age at the time of the earthquake. The adjusted detection rates of cytologically diagnosed malignancy or suspected malignancy were calculated with the implementation rate of secondary confirmatory examinations as follows: The adjusted detection rate = (the number of subjects with cytologically diagnosed malignancy or suspected malignancy/the number of all subjects) × (the number of all subjects recommended for the secondary confirmatory examinations/the number of subjects who completed the secondary confirmatory examinations). We used logistic regression analysis to assess the associations between the prevalence of thyroid cysts, nodules, and cancers, and between age and sex. Nonparametric Spearman’s correlation matrix coefficient was estimated between age and a series of the greatest dimension of thyroid cyst or nodule. The sex difference in the greatest dimension of thyroid cyst or nodule was analyzed by analysis of covariance, adjusted for age. JMP version 10.0.2 (SAS Institute, Cary, NC) was used for statistical analyses. We considered P < 0.05 to be statistically significant. Results Table 1 and Supplemental Fig. 1 show the age- and sex-specific detection rates and multifocality of thyroid cysts. In total, the detection rates of thyroid cysts were 45.7% and 50.0% in male and female subjects, respectively. There was a significant difference between male and female subjects (P < 0.001). The proportion of subjects with cysts increased with age from 1 to 10 years of age, reached a peak at 11 to 12 years of age, and decreased with age from the age of 13 years or older in both sexes. The ages showing the highest detection rates (55.3% and 60.9%) were 11 and 12 years in male and female subjects, respectively. The stratification of age into the groups of 0 to 11 and 12 to 21 years exhibited a statistically significant upward trend in the younger group (P < 0.0001) and a significant downward trend in the older group (P < 0.0001). Multifocal cysts were observed in 89.3% and 89.6% of subjects with thyroid cysts in male and female subjects, respectively. The multifocality of cysts increased with age from 1 to 6 years and then became constant at 7 years of age or older in male and female subjects. Other than at 1 year, there were no differences regarding multifocality in all ages. Table 1. Detection Rate and Multifocality of Thyroid Cysts According to Sex and Age at Examination Age at Examination (y)  Male Subjects  Female Subjects  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  0  160  0  0.0    138  2  1.4  0.0  1  1887  63  3.3  49.2  1753  53  3.0  64.2  2  5009  373  7.4  68.4  4740  405  8.5  72.0  3  6670  984  14.8  77.7  6311  1058  16.8  79.2  4  6916  1677  24.2  84.8  6543  1787  27.3  84.1  5  7177  2361  32.9  87.2  6896  2472  35.8  87.6  6  8541  3545  41.5  89.4  8076  3571  44.2  90.2  7  8681  4120  47.5  90.3  8208  4243  51.7  91.1  8  8770  4582  52.2  91.2  8548  4661  54.5  92.2  9  9164  5001  54.6  92.7  8757  5112  58.4  91.8  10  9559  5271  55.1  91.5  8861  5281  59.6  92.2  11  9647  5335  55.3  91.4  9389  5671  60.4  92.6  12  9996  5503  55.1  91.2  9357  5698  60.9  92.4  13  9746  5297  54.4  90.9  9407  5677  60.3  91.7  14  9986  5381  53.9  90.5  9514  5742  60.4  91.3  15  7826  4103  52.4  88.8  7706  4522  58.7  89.6  16  7402  3903  52.7  88.6  7649  4347  56.8  88.4  17  7572  3742  49.4  87.1  7697  4235  55.0  87.5  18  6065  2872  47.4  85.7  6482  3356  51.8  84.8  19  4568  2160  47.3  86.3  5557  2787  50.2  84.7  ≥20  3488  1736  49.8  84.6  4486  2334  52.0  83.9  Total  148,830  68,009  45.7  89.3  146,075  73,014  50.0  89.6  Age at Examination (y)  Male Subjects  Female Subjects  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  0  160  0  0.0    138  2  1.4  0.0  1  1887  63  3.3  49.2  1753  53  3.0  64.2  2  5009  373  7.4  68.4  4740  405  8.5  72.0  3  6670  984  14.8  77.7  6311  1058  16.8  79.2  4  6916  1677  24.2  84.8  6543  1787  27.3  84.1  5  7177  2361  32.9  87.2  6896  2472  35.8  87.6  6  8541  3545  41.5  89.4  8076  3571  44.2  90.2  7  8681  4120  47.5  90.3  8208  4243  51.7  91.1  8  8770  4582  52.2  91.2  8548  4661  54.5  92.2  9  9164  5001  54.6  92.7  8757  5112  58.4  91.8  10  9559  5271  55.1  91.5  8861  5281  59.6  92.2  11  9647  5335  55.3  91.4  9389  5671  60.4  92.6  12  9996  5503  55.1  91.2  9357  5698  60.9  92.4  13  9746  5297  54.4  90.9  9407  5677  60.3  91.7  14  9986  5381  53.9  90.5  9514  5742  60.4  91.3  15  7826  4103  52.4  88.8  7706  4522  58.7  89.6  16  7402  3903  52.7  88.6  7649  4347  56.8  88.4  17  7572  3742  49.4  87.1  7697  4235  55.0  87.5  18  6065  2872  47.4  85.7  6482  3356  51.8  84.8  19  4568  2160  47.3  86.3  5557  2787  50.2  84.7  ≥20  3488  1736  49.8  84.6  4486  2334  52.0  83.9  Total  148,830  68,009  45.7  89.3  146,075  73,014  50.0  89.6  View Large To investigate the detection rate of thyroid cysts within each size range, we classified the cysts into four categories according to the maximum diameter (≤3.0, 3.1 to 5.0, 5.1 to 20.0, and ≥20.1 mm) (Table 2). In participants with multiple cysts, the maximum diameter of the largest cyst was subjected to this analysis. The proportion of participants with cysts ≤3.0 mm increased with age from 1 to 7 years, reached a peak (∼40%) at age 8 to 9 years, and then decreased with age from 10 years of age onward in male subjects. The same tendency was observed in female subjects. The proportion of participants with cysts 3.1 to 5.0 mm increased with age from 1 to 16 years of age and then became constant at 17 years of age onward in male and female subjects. The proportion of participants with cysts 5.1 to 20.0 mm gradually increased with age from 1 to 19 years and was higher in female subjects than in male subjects of all ages. Cysts ≥20.1 mm were rare in both sexes. There were age-dependent increases in the median cyst diameters in both sexes (male: r = 0.343, P < 0.0001; female: r = 0.378, P < 0.0001), in which a significant sex difference was evident (P < 0.0001 adjusted for age). Table 2. Age- and Sex-Dependent Detection Rate and Median of Thyroid Cysts Age at Examination (y)  Male Subjects  Female Subjects  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  0  0.00  0.00  0.00  0.00    0.00  1.45  0.00  0.00  4.2  1  2.54  0.74  0.05  0.00  2.2  2.80  0.17  0.06  0.00  2.0  2  6.51  0.88  0.06  0.00  2.0  7.30  1.12  0.13  0.00  2.0  3  13.19  1.41  0.15  0.00  2.0  14.44  2.14  0.19  0.00  2.1  4  21.78  2.31  0.16  0.00  2.1  23.52  3.59  0.20  0.00  2.1  5  27.99  4.77  0.14  0.00  2.2  30.54  5.10  0.20  0.00  2.2  6  34.29  6.91  0.30  0.00  2.2  37.10  6.76  0.36  0.00  2.3  7  37.98  9.02  0.46  0.00  2.3  40.00  11.15  0.55  0.00  2.4  8  39.97  11.72  0.56  0.00  2.5  40.86  13.07  0.60  0.00  2.5  9  40.78  13.14  0.65  0.00  2.5  41.26  16.08  1.04  0.00  2.6  10  39.61  14.53  1.00  0.00  2.5  38.04  19.86  1.69  0.00  2.7  11  38.00  16.10  1.20  0.00  2.6  35.42  22.62  2.34  0.01  2.8  12  34.80  18.57  1.68  0.00  2.7  31.86  25.70  3.33  0.00  3.0  13  32.04  20.04  2.26  0.01  2.8  28.68  27.47  4.20  0.00  3.1  14  29.82  21.27  2.78  0.01  2.9  27.33  27.69  5.34  0.00  3.2  15  26.59  22.78  3.05  0.00  3.0  25.23  27.52  5.93  0.00  3.2  16  25.99  23.17  3.57  0.00  3.1  23.78  26.60  6.42  0.03  3.3  17  23.89  21.32  4.20  0.01  3.1  22.32  25.58  7.09  0.03  3.3  18  22.29  21.27  3.79  0.00  3.1  20.21  24.27  7.30  0.00  3.4  19  21.10  21.02  5.17  0.00  3.2  19.13  22.87  8.13  0.02  3.4  ≥20  22.31  22.59  5.79  0.00  3.2  20.78  23.00  8.18  0.07  3.4  Total  22.28  22.65  4.85  0.00  2.7  28.82  17.99  3.17  0.01  2.8  Age at Examination (y)  Male Subjects  Female Subjects  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  0  0.00  0.00  0.00  0.00    0.00  1.45  0.00  0.00  4.2  1  2.54  0.74  0.05  0.00  2.2  2.80  0.17  0.06  0.00  2.0  2  6.51  0.88  0.06  0.00  2.0  7.30  1.12  0.13  0.00  2.0  3  13.19  1.41  0.15  0.00  2.0  14.44  2.14  0.19  0.00  2.1  4  21.78  2.31  0.16  0.00  2.1  23.52  3.59  0.20  0.00  2.1  5  27.99  4.77  0.14  0.00  2.2  30.54  5.10  0.20  0.00  2.2  6  34.29  6.91  0.30  0.00  2.2  37.10  6.76  0.36  0.00  2.3  7  37.98  9.02  0.46  0.00  2.3  40.00  11.15  0.55  0.00  2.4  8  39.97  11.72  0.56  0.00  2.5  40.86  13.07  0.60  0.00  2.5  9  40.78  13.14  0.65  0.00  2.5  41.26  16.08  1.04  0.00  2.6  10  39.61  14.53  1.00  0.00  2.5  38.04  19.86  1.69  0.00  2.7  11  38.00  16.10  1.20  0.00  2.6  35.42  22.62  2.34  0.01  2.8  12  34.80  18.57  1.68  0.00  2.7  31.86  25.70  3.33  0.00  3.0  13  32.04  20.04  2.26  0.01  2.8  28.68  27.47  4.20  0.00  3.1  14  29.82  21.27  2.78  0.01  2.9  27.33  27.69  5.34  0.00  3.2  15  26.59  22.78  3.05  0.00  3.0  25.23  27.52  5.93  0.00  3.2  16  25.99  23.17  3.57  0.00  3.1  23.78  26.60  6.42  0.03  3.3  17  23.89  21.32  4.20  0.01  3.1  22.32  25.58  7.09  0.03  3.3  18  22.29  21.27  3.79  0.00  3.1  20.21  24.27  7.30  0.00  3.4  19  21.10  21.02  5.17  0.00  3.2  19.13  22.87  8.13  0.02  3.4  ≥20  22.31  22.59  5.79  0.00  3.2  20.78  23.00  8.18  0.07  3.4  Total  22.28  22.65  4.85  0.00  2.7  28.82  17.99  3.17  0.01  2.8  Thyroid cysts were classified into four categories according to maximum diameter (≤3.0, 3.1–5.0, 5.1–20.0, and ≥20.1 mm). View Large Table 3 and Supplemental Fig. 2 show the age- and sex-specific detection rates and multifocality of thyroid nodules. Subjects with thyroid nodules included both subjects with benign and malignant nodules. In total, the detection rates of thyroid nodules were 1.0% and 1.7% in male and female subjects, respectively. There was a significant difference between male and female subjects (P < 0.001). Thyroid cysts were also detected in 48.8% and 52.5% of subjects with thyroid nodules in male and female subjects, respectively. A proportional increment in the detection rate of thyroid nodules with age was observed in either sex (P < 0.0001). An evident sex difference was observed in subjects aged 10 years or older. An age-dependent increase in the detection rate started at age 10 years in female subjects, at which point it reached 1.0%. In male subjects, an apparent increase appeared after the age of 14 years, at which point the detection rate was 1.0%. The group aged 20 years or older exhibited the highest detection rates (3.5% and 6.7% in male and female subjects, respectively). Multifocal nodules were observed in 13.0% and 15.0% of subjects with thyroid nodules in male and female subjects, respectively. The multifocality of nodules was consistently higher than 10% from the age of 7 years in both sexes. Table 3. Detection Rate and Multifocality of Thyroid Nodules According to Sex and Age at Examination Age at Examination (y)  Male Subjects  Female Subjects  n  Detection Rate (%)  Multifocality (%)  n  Detection Rate (%)  Multifocality (%)  0  0  0.0    0  0.0    1  6  0.3  0.0  8  0.5  12.5  2  21  0.4  4.8  10  0.2  0.0  3  12  0.2  0.0  24  0.4  8.3  4  35  0.5  14.3  24  0.4  20.8  5  33  0.5  3.0  20  0.3  5.0  6  39  0.5  2.6  34  0.4  17.6  7  42  0.5  14.3  45  0.5  11.1  8  47  0.5  12.8  58  0.7  15.5  9  46  0.5  15.2  56  0.6  7.1  10  56  0.6  10.7  92  1.0  20.7  11  66  0.7  15.2  110  1.2  13.6  12  75  0.8  16.0  151  1.6  15.9  13  88  0.9  13.6  165  1.8  15.2  14  102  1.0  14.7  170  1.8  14.7  15  109  1.0  11.9  189  2.5  10.1  16  114  1.5  17.5  216  2.8  15.7  17  126  1.7  9.5  274  3.6  13.9  18  159  2.6  11.3  245  3.8  13.9  19  117  2.6  13.7  265  4.8  16.2  ≥20  122  3.5  18.9  299  6.7  19.7  Total  1415  1.0  13.0  2455  1.7  15.0  Age at Examination (y)  Male Subjects  Female Subjects  n  Detection Rate (%)  Multifocality (%)  n  Detection Rate (%)  Multifocality (%)  0  0  0.0    0  0.0    1  6  0.3  0.0  8  0.5  12.5  2  21  0.4  4.8  10  0.2  0.0  3  12  0.2  0.0  24  0.4  8.3  4  35  0.5  14.3  24  0.4  20.8  5  33  0.5  3.0  20  0.3  5.0  6  39  0.5  2.6  34  0.4  17.6  7  42  0.5  14.3  45  0.5  11.1  8  47  0.5  12.8  58  0.7  15.5  9  46  0.5  15.2  56  0.6  7.1  10  56  0.6  10.7  92  1.0  20.7  11  66  0.7  15.2  110  1.2  13.6  12  75  0.8  16.0  151  1.6  15.9  13  88  0.9  13.6  165  1.8  15.2  14  102  1.0  14.7  170  1.8  14.7  15  109  1.0  11.9  189  2.5  10.1  16  114  1.5  17.5  216  2.8  15.7  17  126  1.7  9.5  274  3.6  13.9  18  159  2.6  11.3  245  3.8  13.9  19  117  2.6  13.7  265  4.8  16.2  ≥20  122  3.5  18.9  299  6.7  19.7  Total  1415  1.0  13.0  2455  1.7  15.0  View Large To analyze the detection rates of thyroid nodules within each size range, we classified the nodules into four categories according to each nodule’s maximum diameter (≤5.0, 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm) and divided the subjects into five groups according to age (0 to 4, 5 to 9, 10 to 14, 15 to 19, and ≥20 years) (Table 4). In participants with multiple nodules, the maximum diameter of the largest nodule was subjected to this analysis. Although nodules in the ≤5.0 mm category were predominant in both sexes below the age of 10 years, nodules within 5.1 to 10.0 mm were predominant in the age groups 10 to 14, 15 to 19, and ≥20 years. An age-dependent increase in the detection rate in all size groups in both sexes and obvious increments in all size groups appeared in the age groups of 10 to 14 and 15 to 19 years in female and male subjects, respectively. This difference in the age shifting to an upward trend in male and female subjects resulted in a sex difference in the detection rate in the 10- to 14-year age group and older. In addition, there were age-dependent increases in the median of nodule diameters in both sexes (male: r = 0.316, P < 0.0001; female: r = 0.190, P < 0.0001) in which no sex differences were evident (P > 0.05 for adjusted for age). Table 4. Age- and Sex-Dependent Detection Rate and Median of Thyroid Nodules Age at Examination (y)  Male Subjects  Female Subjects  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  0–4  20,642  0.30  0.05  0.01  0.00  0.36  4.0  19,485  0.26  0.06  0.02  0.00  0.34  3.6  5–9  42,333  0.34  0.10  0.04  0.00  0.49  4.3  40,485  0.34  0.16  0.03  0.00  0.53  4.2  10–14  48,934  0.42  0.30  0.06  0.01  0.79  4.8  46,528  0.61  0.61  0.21  0.05  1.48  5.7  15–19  33,433  0.68  0.87  0.25  0.07  1.87  6.0  35,091  1.17  1.48  0.60  0.14  3.39  6.2  ≥20  3488  1.06  1.83  0.49  0.11  3.50  6.4  4486  2.36  2.81  1.27  0.22  6.67  6.1  Total  148,830  0.45  0.37  0.10  0.02  0.95  5.2  146,075  0.68  0.69  0.26  0.06  1.68  5.8  Age at Examination (y)  Male Subjects  Female Subjects  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  0–4  20,642  0.30  0.05  0.01  0.00  0.36  4.0  19,485  0.26  0.06  0.02  0.00  0.34  3.6  5–9  42,333  0.34  0.10  0.04  0.00  0.49  4.3  40,485  0.34  0.16  0.03  0.00  0.53  4.2  10–14  48,934  0.42  0.30  0.06  0.01  0.79  4.8  46,528  0.61  0.61  0.21  0.05  1.48  5.7  15–19  33,433  0.68  0.87  0.25  0.07  1.87  6.0  35,091  1.17  1.48  0.60  0.14  3.39  6.2  ≥20  3488  1.06  1.83  0.49  0.11  3.50  6.4  4486  2.36  2.81  1.27  0.22  6.67  6.1  Total  148,830  0.45  0.37  0.10  0.02  0.95  5.2  146,075  0.68  0.69  0.26  0.06  1.68  5.8  Thyroid nodules were classified into four categories according to maximum diameter (≤5.0, 5.1–10.0, 10.1–20.0, and ≥20.1 mm). View Large In total, 746 male and 1478 female participants who had nodules ≥5.1 mm or cysts ≥20.1 mm were recommended to have a secondary confirmatory examination. As of March 2016, 91.6% and 91.3% of male and female subjects had undergone this examination, respectively. FNAC was performed in 174 male and 367 female participants whose sonographic findings in precise ultrasound examination met the criteria for performing FNAC (14). In total, 112 cases (38 in male subjects and 74 in female subjects) were cytologically diagnosed as malignancy or suspected malignancy. Table 5 and Supplemental Fig. 3 show the age and sex distribution of the detection rates of thyroid nodules that were cytologically diagnosed as malignancy or suspected malignancy. The adjusted detection rate corrected by the implementation rate of secondary confirmatory examinations is shown in Table 5. This rate was 0 up to the age of 13 years for male subjects and 8 years for female subjects and then showed significant upward trends in male and female subjects (P < 0.0001) that were higher in female subjects than in male subjects (P = 0.0036). Table 5. Age and Sex Distribution of Detection Rates of Thyroid Nodules Cytologically Diagnosed as Malignancy or Suspected Malignancy Age at Examination (y)  Male Subjects  Female Subjects  No.  Detection Rate (%)  Adjusted Rate (%)  n  Detection Rate (%)  Adjusted Rate (%)  0  0  0.000    0  0.000    1  0  0.000    0  0.000  0.000  2  0  0.000  0.000  0  0.000  0.000  3  0  0.000  0.000  0  0.000  0.000  4  0  0.000  0.000  0  0.000  0.000  5  0  0.000  0.000  0  0.000  0.000  6  0  0.000  0.000  0  0.000  0.000  7  0  0.000  0.000  0  0.000  0.000  8  0  0.000  0.000  1  0.012  0.013  9  0  0.000  0.000  0  0.000  0.000  10  0  0.000  0.000  1  0.011  0.012  11  0  0.000  0.000  3  0.032  0.035  12  0  0.000  0.000  2  0.021  0.024  13  4  0.041  0.043  2  0.021  0.023  14  3  0.030  0.032  6  0.063  0.071  15  5  0.064  0.068  8  0.104  0.112  16  3  0.041  0.041  5  0.065  0.071  17  3  0.040  0.042  11  0.143  0.154  18  10  0.165  0.188  9  0.139  0.154  19  7  0.153  0.170  15  0.270  0.299  ≥20  3  0.086  0.106  11  0.245  0.281  Total  38  0.026  0.028  74  0.051  0.056  Age at Examination (y)  Male Subjects  Female Subjects  No.  Detection Rate (%)  Adjusted Rate (%)  n  Detection Rate (%)  Adjusted Rate (%)  0  0  0.000    0  0.000    1  0  0.000    0  0.000  0.000  2  0  0.000  0.000  0  0.000  0.000  3  0  0.000  0.000  0  0.000  0.000  4  0  0.000  0.000  0  0.000  0.000  5  0  0.000  0.000  0  0.000  0.000  6  0  0.000  0.000  0  0.000  0.000  7  0  0.000  0.000  0  0.000  0.000  8  0  0.000  0.000  1  0.012  0.013  9  0  0.000  0.000  0  0.000  0.000  10  0  0.000  0.000  1  0.011  0.012  11  0  0.000  0.000  3  0.032  0.035  12  0  0.000  0.000  2  0.021  0.024  13  4  0.041  0.043  2  0.021  0.023  14  3  0.030  0.032  6  0.063  0.071  15  5  0.064  0.068  8  0.104  0.112  16  3  0.041  0.041  5  0.065  0.071  17  3  0.040  0.042  11  0.143  0.154  18  10  0.165  0.188  9  0.139  0.154  19  7  0.153  0.170  15  0.270  0.299  ≥20  3  0.086  0.106  11  0.245  0.281  Total  38  0.026  0.028  74  0.051  0.056  The adjusted detection rate is the detection rate corrected by the implementation rate of secondary confirmatory examinations. View Large To analyze the detection rate of thyroid nodules that had been cytologically diagnosed as malignancy or suspected malignancy within each size range, we classified the nodules into four categories according to the maximum diameter measured in the secondary confirmatory examination (≤5.0, 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm) (Table 6). There was a limited number of male subjects with thyroid cancer, so we demonstrated the detection rates not according to sex. No malignant nodules ≤5.0 mm were found in any age group because participants with nodules of ≤5.0 mm had not been recommended for the secondary confirmatory examinations or FNAC. There was an age-dependent increase in the adjusted detection rates of malignant nodules in three categories (5.1 to 10.0, 10.1 to 20.0, and ≥20 mm), but that in the 5.1 to 10.0 mm category reached a plateau in the ≥20 group. In addition, there were age-dependent increases in the median of nodule diameters (r = 0.246, P < 0.0001). Table 6. Detection Rate of Classified by Size Categories and Median Diameter of Thyroid Nodules Cytologically Diagnosed as Malignancy or Suspected Malignancy Age at Examination (y)  Detection Rate (%)  Adjusted Detection Rate (%)  Median (mm)  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  0–4  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000    5–9  0.000  0.000  0.001  0.000  0.001  0.000  0.000  0.001  0.000  0.001  12.0  10–14  0.000  0.005  0.013  0.004  0.022  0.000  0.006  0.014  0.005  0.024  12.3  15–19  0.000  0.045  0.050  0.016  0.111  0.000  0.049  0.054  0.017  0.121  11.5  ≥20  0.000  0.038  0.088  0.050  0.176  0.000  0.044  0.103  0.059  0.206  14.9  Total  0.000  0.013  0.018  0.006  0.038  0.000  0.014  0.020  0.007  0.042  12.4  Age at Examination (y)  Detection Rate (%)  Adjusted Detection Rate (%)  Median (mm)  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  0–4  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000    5–9  0.000  0.000  0.001  0.000  0.001  0.000  0.000  0.001  0.000  0.001  12.0  10–14  0.000  0.005  0.013  0.004  0.022  0.000  0.006  0.014  0.005  0.024  12.3  15–19  0.000  0.045  0.050  0.016  0.111  0.000  0.049  0.054  0.017  0.121  11.5  ≥20  0.000  0.038  0.088  0.050  0.176  0.000  0.044  0.103  0.059  0.206  14.9  Total  0.000  0.013  0.018  0.006  0.038  0.000  0.014  0.020  0.007  0.042  12.4  The adjusted detection rate is the detection rate corrected by the implementation rate of secondary confirmatory examinations. Thyroid nodules were classified into four categories according to maximum diameter (≤5.0, 5.1–10.0, 10.1–20.0, and ≥20.1 mm). View Large Nodules cytologically diagnosed as malignancy or suspected malignancy within 10.1 to 20.0 mm were predominant in the age groups of 10 to 14, 15 to 19, and ≥20 years. However, these detection rates were influenced by the implementation criteria for FNAC (12, 14). The proportions of the estimated number of subjects with nodules cytologically diagnosed as malignancy or suspected malignancy to the number of subjects with nodules were 2.7%, 11.0%, and 17.8% in the categories of 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm, respectively. Discussion We report the detailed age and sex distribution of findings from TUEs among children and adolescents, which were conducted as the first-round examination of the FHMS within 3 years of the Fukushima nuclear power plant accident. The examination results varied substantially by age group. A thyroid colloid cyst is a common benign thyroid lesion showing marked follicular dilatation and epithelial flattening (15). In our study, the mixed solid-cystic type tumor, which is a cyst with a solid component, was not classified as a cyst; instead, it was classified as a nodule because this mixed-type tumor sometimes occurs in thyroid cancer. Therefore, most of thyroid cysts in this study had no pathological significance. Few reports have studied the prevalence of thyroid cysts in children and adolescents. In the area surrounding Chernobyl, ultrasound examination of thyroid glands revealed that 502 of the 120,605 children examined had cystic lesions, a prevalence rate of only 0.42% (16). Technical advances in ultrasound equipment have led to the detection of small nodules and cysts and to an increase in prevalence rates. Avula et al. (17) conducted a retrospective analysis of clinical and ultrasound findings in 287 Canadian children aged 0 to 17 years between 2006 and 2007 and detected incidental thyroid findings in 52 children (18%). Among these incidental thyroid findings, 35 were small (<4 mm), well-defined cysts, and the prevalence rate was 12%. The Investigation Committee for the Proportion of Thyroid Ultrasound Findings in Japan Association of Breast and Thyroid Sonology studied the prevalence rate of thyroid nodular lesions detected using high-resolution sonography in a general population of Japanese children living in three prefectures located far from Fukushima (9, 10). The subjects of that study were children and adolescents aged between 3 and 18 years, and it was revealed that the prevalence rate of thyroid cysts was 56.5%, which appears to be higher than that of the current study. The bias in subjects’ age in the three-prefecture study might account for the difference in the prevalence rate; no children aged 0 to 2 years, and only a small number of children aged 3 to 5 years, were recruited (9). As shown in the current study, children aged 0 to 5 years exhibited a relatively low prevalence rate. The proportion of participants who had cysts of ≤3.0 mm increased from age 0 to 10 years and decreased thereafter until the age of 20 years, whereas the proportion of those who had cysts of 3.1 to 5.0 and 5.1 to 20.0 mm, as well as the median size of cysts, increased with age. These findings may imply that some cysts that are ≤3.0 mm may regress and disappear within a short period, but this is not the case with larger cysts. In contrast, the detection rate of thyroid nodules in all size categories showed an age-dependent increase. Thyroid nodules are common in adult patients but not in children or adolescents. Numerous studies suggest that the prevalence of thyroid nodules largely depends on the method of examination, with a prevalence of 2% to 6% with palpation, 19% to 35% with ultrasound, and 8% to 65% in autopsy data (18). In contrast to adults, much less is known about the prevalence of thyroid nodules in the general population of children. Rallison et al. (19) examined 5179 school children in Utah, Nevada, and Arizona for thyroid abnormalities because of possible exposure to radiation from fallout. Palpation of the thyroid gland found nodularity of the thyroid in 98 (1.8%) subjects. In addition, a retrospective study using ultrasound was reported by Avula et al. (17). Of 287 children, 9 (3.1%) had hypoechoic solid nodules with smooth straight margins and tiny hyperechoic foci, which were considered to be intrathyroid ectopic thymus. Three nodules (1.0%), two (0.7%) of which had target-like findings suggesting cystic nodules and one (0.3%) of which was an isoechoic well-defined nodule, were found. In another study, Aghini-Lombardi et al. (20) also reported that thyroid nodular goiter was found in 0.5% of children (1 to 14 years old) and in 2.1% of adolescents and young adults aged 15 to 25 years. The Investigation Committee for the Proportion of Thyroid Ultrasound Findings revealed that the prevalence of thyroid nodules in Japanese children between 3 and 18 years was 1.6%, and the age-adjusted prevalence of thyroid nodules was 1.54% (9, 10). These results are quite similar to the outcomes from the TUE in Fukushima presented in the current study, in which the detection rates of thyroid nodules were 1.0% and 1.7% in male and female subjects, respectively. Similar age dependency regarding the prevalence of thyroid cysts and nodules to that in this study was shown in a study by The Investigation Committee for the Proportion of Thyroid Ultrasound Findings, in which TUE for children was conducted using the same procedure used in the current study in three Japanese prefectures (Aomori, Yamanashi, and Nagasaki) (9, 10). The proportions of those with cysts in the age groups 3 to 4, 5 to 9, 10 to 14, and 15 to 18 years in that study were 19.7%, 49.1%, 60.5%, and 59.5%, respectively, for male and female subjects combined (10). The corresponding proportions in the current study are similar: 20.8%, 47.9%, 57.5%, and 53.2%, respectively. The proportions of those with nodules in the age groups of 3 to 4, 5 to 9, 10 to 14, and 15 to 18 years were 1.41%, 0.64%, 1.50%, and 2.69%, respectively, for male and female subjects combined (10). In the age group of 3 to 4 years, there was a lack of reliability in the detection rate because only one subject with malignancy or suspected malignancy was found in this group. The corresponding proportions for the same age groups in the current study were also similar (0.36%, 0.51%, 1.13%, and 2.45%, respectively). In the current study, the detection rates of thyroid cysts and nodules in female subjects were higher than those in male subjects. However, the difference between sexes in the prevalence of cysts was clearly smaller than that of thyroid nodules. A similar tendency in sex difference in the prevalence of thyroid cysts and nodules has been shown in previous reports (9, 10). Hayashida et al. (10) reported that the prevalence of thyroid cysts and nodules in male and female subjects was 53.4% to 60.0% and 1.20% to 2.05%, respectively. In addition, the current study showed a sex difference in the detection rate of nodules in participants aged 10 years or older. That the age of 10 years in female subjects almost coincides with the onset of puberty suggests that the sex difference during puberty might be induced by estrogen-dependent stimulation of thyroid cell proliferation (21). Thyroid cancer in the youngest age group among this baseline survey was detected only in subjects aged 13 years for male subjects and 8 years for female subjects. The adjusted detection rate increased with age and was higher in female subjects than in male subjects. A difference between the sexes was evident after the age of 14 years, and the overall adjusted detection rate of thyroid cancer was 0.028% and 0.056% in male and female subjects, respectively. Few reports studying the prevalence of thyroid cancer in children and adolescents are available. Screening of thyroid disease by palpation revealed thyroid cancer in 2 of 5179 school children aged 11 to 18 years in Utah, Nevada, and Arizona (19). In that study, the prevalence rate of thyroid cancer was 0.04%. A Ukraine–US cohort study conducted after the Chernobyl accident reported that the detection of thyroid cancer during the first screening from 1998 to 2000 was 0.149% in the control group (<200 mSv dose category) by palpation and/or ultrasound targeting subjects aged 12 to 33 years (average, 24.7 years) (22). A Belarus–US cohort study after the Chernobyl disaster has also shown that the detection of thyroid cancer during the first screening from 1996 to 2001 was 0.301% in the control group (<50-mSv dose category) by palpation or ultrasound, targeting subjects aged 10 to 33 years (23). The Investigation Committee for the Proportion of Thyroid Ultrasound Findings in Japan performed a secondary confirmatory examination study for subjects with nodules ≥5.1 mm or cysts ≥20.1 mm selected from the cohort of 4365 children aged 3 to 18 years (11). In total, 31 of 44 children with nodules ≥5.1 mm or cysts ≥20.1 mm agreed to be enrolled in this study, and one subject was diagnosed with papillary thyroid carcinoma (11). These findings suggest that the adjusted detection rate corrected by the implementation rate of secondary confirmatory examinations was 0.03%. An age-dependent increase in the incidence of thyroid cancer has been reported by the national cancer registry in Japan and the United States (24, 25) and in the number of childhood patients with thyroid carcinoma in single institutions (26, 27). In contrast, the incidence of pediatric thyroid cancer in the Republic of Belarus after the Chernobyl disaster was shown to be higher in the younger population. The highest number of patients that subsequently developed thyroid cancer was in the age group of younger than 1 year at the time of the accident. A study of A-bomb survivors exposed in childhood reported that not only thyroid cancer but also benign nodules and cysts were associated with thyroid radiation dose (28). Although the sensitivity and quality control of diagnostic criteria should be carefully considered in addition to other confounding factors on thyroid carcinogenesis, it is important to observe the frequency of thyroid benign nodules and cysts when investigating the association between radiation exposure and thyroid cancer in childhood. There were some limitations to this study. First, the findings may not be completely comparable to other populations with a different diet/environment and different ethnicity. For example, the prevalence of thyroid nodules depends on the amount of iodine intake. It was reported that even small changes in iodine intake from mandatory iodination of table and bread salt significantly influence goiter prevalence, nodule incidence, and thyroid dysfunction and raise the risk of thyroid nodules (18). Residents of Japan have high iodine intake associated with frequent consumption of seaweed (29). Second, we could not record the distribution of the number of lesions in the cases with multiple lesions because we had to perform ultrasound examinations for the large number of young residents with a limited number of examiners within 2.5 years. In addition, some subjects with multiple cysts showed many small colloid cysts. Finally, this study had no control cohort with a similar number of subjects. The Chernobyl nuclear accident occurred in 1986, and the incidence of childhood thyroid cancer in Belarus has exhibited an elevation since 1990 (30). Thus, the expected latency for radiation-induced thyroid cancer is considered to be 4 to 5 years (14). In the current study, the fact that the examination period was within 3 years after the nuclear accident suggests that this study was performed before any radiation-induced influence. Additionally, a study with a small number of subjects residing in other regions of Japan reported reference data (9, 10). This study showed similar prevalence rates of thyroid cysts and nodules. In summary, the accurate prevalence of the findings of thyroid abnormalities and information on age dependence in neonates to adolescents has been clarified in Fukushima following the introduction of a highly sophisticated methodology that can easily detect small and asymptomatic thyroid abnormalities. Because the mechanisms of occurrence and growth of thyroid cancer, nodules, and cysts in children and adolescents have not been not sufficiently analyzed, further long-term follow-up of ultrasound examination is a key issue, including the results from the second and future rounds of examination, which was started in April 2014. Abbreviations: FHMS Fukushima Health Management Survey FNAC fine-needle aspiration cytology TUE thyroid ultrasound examination. Acknowledgments Other participating expert committee members, advisors, and staff members in the Fukushima Health Management Survey: Kenji Kamiya, Kenneth E. Nollet, Kumiko Tsuboi, Shiro Matsui, Seisho Tanaka, Masaharu Maeda, Shigeatsu Hashimoto, Keiya Fujimori, Suguru Ishida, Testuo Ishikawa, Akira, Sakai, Yuko Hino, Hiroshi Mizunuma, Keiichi Nakano, Satoshi Suzuki, Chiyo Ohkouchi, Tomomi Hakoiwa, Chisato Takahashi, Yukari Sato, Ayako Sato, Nobuko Sakuma, Toshie Sakagami, Manabu Ohishi, Norikazu Abe, Masahiko Henmi, Yukie Yamaya, Takao Yamahata, Yukiko Horikoshi, Yoko Nihei, Risa Ujiie, Sakiko Meguro, Ayana Okazaki, Yumiko Kurozu, Mizuki Sekino, Yuko Sato, and Yayoi Sato. The authors thank the staff of the Fukushima Health Management Survey for their important contributions. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Fukushima prefectural government. Financial Support: This work was supported by the National Health Fund for Children and Adults Affected by the Nuclear Incident for the design and conduct of the study. 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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2017-01603
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Abstract

Abstract Context Childhood thyroid cancer is of great concern after the Fukushima nuclear power plant accident. Baseline analytical data on thyroid ultrasound examination (TUE) in children are important for future studies. Objective We analyzed the age and sex distribution of findings from the TUEs of children and adolescents in the Fukushima Health Management Survey (FHMS). Design, Setting, and Participants From October 2011 through March 2014, 294,905 participants aged 18 years or younger at the time of the earthquake voluntarily had TUEs in the first round of the FHMS. A secondary confirmatory examination was performed in 2032 subjects. Age- and sex-dependent prevalence and size of thyroid cysts, nodules, and cancers were analyzed. Main Outcome Measures Age, sex, and size distribution of findings were analyzed. Results Thyroid cysts, nodules, and cytologically suspected cancers were detected in 68,009, 1415, and 38 male subjects and in 73,014, 2455, and 74 female subjects, respectively. There was an age-dependent increase in the detection rate of thyroid nodules and cancer, but that of cysts reached a peak at 11 to 12 years. Sex affected the prevalence of thyroid nodules and cancers after the onset of puberty, but only a small difference was exhibited in that of cysts. Conclusions The thyroid cancer detection rate in Fukushima was clarified, and the proportion of individuals with thyroid nodules and cysts varied substantially by age. The results of this study will contribute to future epidemiological research on nodular thyroid diseases in children and adolescents. Childhood thyroid cancer is of great concern in Fukushima Prefecture, and the fear of cancer is prominent throughout Japan because previous studies have reported that one of the main adverse health effects of radiation fallout from nuclear power plant accidents, especially the Chernobyl nuclear power plant accident, has been a substantial rise in thyroid cancer among exposed young people (1–3). Because radiation exposure levels in Fukushima residents were considered to be much lower than those in Chernobyl residents, a large increase in thyroid cancer rates due to radiation exposure, such as that which occurred after the Chernobyl accident, had not been expected (4). However, it was necessary to conduct surveys for both scientific and social demands (5). The Fukushima prefectural government started to examine thyroid glands by using ultrasound examination and common standardized diagnostic criteria among residents aged 18 years or younger from 7 months after the Fukushima Daiichi nuclear power plant accident (5–7) The first-round survey, during the first 3 years after the accident, is evaluated as baseline data prior to the period in which radiation effects on the thyroid gland could potentially occur (5). Because there have been no data on the thyroid ultrasound examination (TUE) among asymptomatic children and adolescents in a population of this size (i.e., hundreds of thousands) (8), it is worthwhile to share some of the findings from the survey. The same examination and diagnostic methods were used in a study of 3- to 18-year-old children performed in three prefectures located far from Fukushima (Aomori, Yamanashi, and Nagasaki), for a total sample size of 4365 (9–11). We report herein the precise age and sex differences in the findings from the TUEs performed on children and adolescents, which was conducted in the first-round examination of the Fukushima Health Management Survey (FHMS). The results demonstrated in this study will serve as reference data for future epidemiological studies of nodular thyroid diseases in children, adolescents, and young adults. Materials and Methods Study population Subjects were inhabitants of Fukushima Prefecture aged between 0 and 18 years on 1 April 2011. The preliminary baseline survey, the first-round of TUE, was conducted from October 2011 through March 2014 as part of the FHMS and was extended to April 2015 to provide an opportunity for nonparticipants to have this examination (5, 7). Among the target population of 367,672, 300,476 subjects (81.7%), including evacuees currently living in other prefectures, voluntarily participated in this survey (12, 13). This study included 294,905 participants who had TUE from October 2011 to March 2014. These subjects were 0 to 18 years of age at the time of the earthquake and 0 to 21 years of age at the time of examination. This survey was approved by the ethics review committee of Fukushima Medical University (no. 1318). Written informed consent was obtained from the parents or guardians of all surveyed children. The raw data used to create all tables in the current study are unavailable due to a restriction outlined in the informed consent. Primary TUE Ultrasound was used to examine the thyroid gland. A detailed protocol has been reported elsewhere (6, 7, 14). In brief, ultrasound examination was conducted using a LOGIQ e Expert (GE Health Care, Tokyo, Japan) with a 12L-RS linear probe (10–12 MHz) and a Noblus (Hitachi-Aloka, Tokyo, Japan) with a 12 MHz linear probe. This highly sophisticated method detects nodules and cysts <1 mm in size and records thyroid volume and other findings, such as congenital defects and ectopic thymus. In subjects with nodules, the examiner recorded the multifocality of nodules and the location of the largest nodule and measured the greatest dimension of the largest nodule. In subjects with cysts, the assessor also recorded the multifocality of the cysts and the location of the largest cyst and measured the greatest dimension of the cysts. In our survey, the mixed solid-cystic type tumor, which is a cyst with a solid component, was not classified as a cyst; it was classified as a nodule because this mixed-type tumor sometimes occurs in thyroid cancer (7). Secondary confirmatory TUE Subjects with nodules ≥5.1 mm or cysts ≥20.1 mm were recommended to undergo a secondary confirmatory examination. Physicians credentialed by the Japan Thyroid Association, Japanese Society of Thyroid Surgery, Japan Society of Ultrasonics in Medicine performed the confirmatory examination using the highest-resolution instrumentation. This confirmatory examination included a precise ultrasound examination, blood and urine tests, and fine-needle aspiration cytology (FNAC) if sonographic findings of nodules or cysts met the FNAC criteria according to the guidelines issued by the Japan Association of Breast and Thyroid Sonology (12, 14). According to guidelines of the Japan Association of Breast and Thyroid Sonology, FNAC is recommended for nodules >5 mm in diameter that are strongly suspicious for thyroid carcinoma using Japan Society of Ultrasonics in Medicine diagnostic criteria (14), nodules >10 mm in diameter and suspicious for carcinoma using the above criteria, nodules >20 mm in diameter, and cystic lesions >20 mm in diameter. These guidelines were followed to avoid unnecessary FNAC, especially for nodules >5 mm but <10 mm. If a benign lesion was detected by ultrasonography only or by ultrasonography and FNAC, the subjects were recommended to undergo a follow-up treatment under Japan’s comprehensive medical coverage program. If a malignancy was suspected or detected by FNAC, the subject would require surgical treatment. Statistical analysis All results shown in this study were analyzed using the subject’s age at time of the primary examination instead of their age at the time of the earthquake. The adjusted detection rates of cytologically diagnosed malignancy or suspected malignancy were calculated with the implementation rate of secondary confirmatory examinations as follows: The adjusted detection rate = (the number of subjects with cytologically diagnosed malignancy or suspected malignancy/the number of all subjects) × (the number of all subjects recommended for the secondary confirmatory examinations/the number of subjects who completed the secondary confirmatory examinations). We used logistic regression analysis to assess the associations between the prevalence of thyroid cysts, nodules, and cancers, and between age and sex. Nonparametric Spearman’s correlation matrix coefficient was estimated between age and a series of the greatest dimension of thyroid cyst or nodule. The sex difference in the greatest dimension of thyroid cyst or nodule was analyzed by analysis of covariance, adjusted for age. JMP version 10.0.2 (SAS Institute, Cary, NC) was used for statistical analyses. We considered P < 0.05 to be statistically significant. Results Table 1 and Supplemental Fig. 1 show the age- and sex-specific detection rates and multifocality of thyroid cysts. In total, the detection rates of thyroid cysts were 45.7% and 50.0% in male and female subjects, respectively. There was a significant difference between male and female subjects (P < 0.001). The proportion of subjects with cysts increased with age from 1 to 10 years of age, reached a peak at 11 to 12 years of age, and decreased with age from the age of 13 years or older in both sexes. The ages showing the highest detection rates (55.3% and 60.9%) were 11 and 12 years in male and female subjects, respectively. The stratification of age into the groups of 0 to 11 and 12 to 21 years exhibited a statistically significant upward trend in the younger group (P < 0.0001) and a significant downward trend in the older group (P < 0.0001). Multifocal cysts were observed in 89.3% and 89.6% of subjects with thyroid cysts in male and female subjects, respectively. The multifocality of cysts increased with age from 1 to 6 years and then became constant at 7 years of age or older in male and female subjects. Other than at 1 year, there were no differences regarding multifocality in all ages. Table 1. Detection Rate and Multifocality of Thyroid Cysts According to Sex and Age at Examination Age at Examination (y)  Male Subjects  Female Subjects  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  0  160  0  0.0    138  2  1.4  0.0  1  1887  63  3.3  49.2  1753  53  3.0  64.2  2  5009  373  7.4  68.4  4740  405  8.5  72.0  3  6670  984  14.8  77.7  6311  1058  16.8  79.2  4  6916  1677  24.2  84.8  6543  1787  27.3  84.1  5  7177  2361  32.9  87.2  6896  2472  35.8  87.6  6  8541  3545  41.5  89.4  8076  3571  44.2  90.2  7  8681  4120  47.5  90.3  8208  4243  51.7  91.1  8  8770  4582  52.2  91.2  8548  4661  54.5  92.2  9  9164  5001  54.6  92.7  8757  5112  58.4  91.8  10  9559  5271  55.1  91.5  8861  5281  59.6  92.2  11  9647  5335  55.3  91.4  9389  5671  60.4  92.6  12  9996  5503  55.1  91.2  9357  5698  60.9  92.4  13  9746  5297  54.4  90.9  9407  5677  60.3  91.7  14  9986  5381  53.9  90.5  9514  5742  60.4  91.3  15  7826  4103  52.4  88.8  7706  4522  58.7  89.6  16  7402  3903  52.7  88.6  7649  4347  56.8  88.4  17  7572  3742  49.4  87.1  7697  4235  55.0  87.5  18  6065  2872  47.4  85.7  6482  3356  51.8  84.8  19  4568  2160  47.3  86.3  5557  2787  50.2  84.7  ≥20  3488  1736  49.8  84.6  4486  2334  52.0  83.9  Total  148,830  68,009  45.7  89.3  146,075  73,014  50.0  89.6  Age at Examination (y)  Male Subjects  Female Subjects  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  No. of Subjects  No. With Cysts  Detection Rate (%)  Multifocality (%)  0  160  0  0.0    138  2  1.4  0.0  1  1887  63  3.3  49.2  1753  53  3.0  64.2  2  5009  373  7.4  68.4  4740  405  8.5  72.0  3  6670  984  14.8  77.7  6311  1058  16.8  79.2  4  6916  1677  24.2  84.8  6543  1787  27.3  84.1  5  7177  2361  32.9  87.2  6896  2472  35.8  87.6  6  8541  3545  41.5  89.4  8076  3571  44.2  90.2  7  8681  4120  47.5  90.3  8208  4243  51.7  91.1  8  8770  4582  52.2  91.2  8548  4661  54.5  92.2  9  9164  5001  54.6  92.7  8757  5112  58.4  91.8  10  9559  5271  55.1  91.5  8861  5281  59.6  92.2  11  9647  5335  55.3  91.4  9389  5671  60.4  92.6  12  9996  5503  55.1  91.2  9357  5698  60.9  92.4  13  9746  5297  54.4  90.9  9407  5677  60.3  91.7  14  9986  5381  53.9  90.5  9514  5742  60.4  91.3  15  7826  4103  52.4  88.8  7706  4522  58.7  89.6  16  7402  3903  52.7  88.6  7649  4347  56.8  88.4  17  7572  3742  49.4  87.1  7697  4235  55.0  87.5  18  6065  2872  47.4  85.7  6482  3356  51.8  84.8  19  4568  2160  47.3  86.3  5557  2787  50.2  84.7  ≥20  3488  1736  49.8  84.6  4486  2334  52.0  83.9  Total  148,830  68,009  45.7  89.3  146,075  73,014  50.0  89.6  View Large To investigate the detection rate of thyroid cysts within each size range, we classified the cysts into four categories according to the maximum diameter (≤3.0, 3.1 to 5.0, 5.1 to 20.0, and ≥20.1 mm) (Table 2). In participants with multiple cysts, the maximum diameter of the largest cyst was subjected to this analysis. The proportion of participants with cysts ≤3.0 mm increased with age from 1 to 7 years, reached a peak (∼40%) at age 8 to 9 years, and then decreased with age from 10 years of age onward in male subjects. The same tendency was observed in female subjects. The proportion of participants with cysts 3.1 to 5.0 mm increased with age from 1 to 16 years of age and then became constant at 17 years of age onward in male and female subjects. The proportion of participants with cysts 5.1 to 20.0 mm gradually increased with age from 1 to 19 years and was higher in female subjects than in male subjects of all ages. Cysts ≥20.1 mm were rare in both sexes. There were age-dependent increases in the median cyst diameters in both sexes (male: r = 0.343, P < 0.0001; female: r = 0.378, P < 0.0001), in which a significant sex difference was evident (P < 0.0001 adjusted for age). Table 2. Age- and Sex-Dependent Detection Rate and Median of Thyroid Cysts Age at Examination (y)  Male Subjects  Female Subjects  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  0  0.00  0.00  0.00  0.00    0.00  1.45  0.00  0.00  4.2  1  2.54  0.74  0.05  0.00  2.2  2.80  0.17  0.06  0.00  2.0  2  6.51  0.88  0.06  0.00  2.0  7.30  1.12  0.13  0.00  2.0  3  13.19  1.41  0.15  0.00  2.0  14.44  2.14  0.19  0.00  2.1  4  21.78  2.31  0.16  0.00  2.1  23.52  3.59  0.20  0.00  2.1  5  27.99  4.77  0.14  0.00  2.2  30.54  5.10  0.20  0.00  2.2  6  34.29  6.91  0.30  0.00  2.2  37.10  6.76  0.36  0.00  2.3  7  37.98  9.02  0.46  0.00  2.3  40.00  11.15  0.55  0.00  2.4  8  39.97  11.72  0.56  0.00  2.5  40.86  13.07  0.60  0.00  2.5  9  40.78  13.14  0.65  0.00  2.5  41.26  16.08  1.04  0.00  2.6  10  39.61  14.53  1.00  0.00  2.5  38.04  19.86  1.69  0.00  2.7  11  38.00  16.10  1.20  0.00  2.6  35.42  22.62  2.34  0.01  2.8  12  34.80  18.57  1.68  0.00  2.7  31.86  25.70  3.33  0.00  3.0  13  32.04  20.04  2.26  0.01  2.8  28.68  27.47  4.20  0.00  3.1  14  29.82  21.27  2.78  0.01  2.9  27.33  27.69  5.34  0.00  3.2  15  26.59  22.78  3.05  0.00  3.0  25.23  27.52  5.93  0.00  3.2  16  25.99  23.17  3.57  0.00  3.1  23.78  26.60  6.42  0.03  3.3  17  23.89  21.32  4.20  0.01  3.1  22.32  25.58  7.09  0.03  3.3  18  22.29  21.27  3.79  0.00  3.1  20.21  24.27  7.30  0.00  3.4  19  21.10  21.02  5.17  0.00  3.2  19.13  22.87  8.13  0.02  3.4  ≥20  22.31  22.59  5.79  0.00  3.2  20.78  23.00  8.18  0.07  3.4  Total  22.28  22.65  4.85  0.00  2.7  28.82  17.99  3.17  0.01  2.8  Age at Examination (y)  Male Subjects  Female Subjects  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  ≤3.0 mm (%)  3.1–5.0 mm (%)  5.1–20.0 mm (%)  ≥20.1 mm (%)  Median  0  0.00  0.00  0.00  0.00    0.00  1.45  0.00  0.00  4.2  1  2.54  0.74  0.05  0.00  2.2  2.80  0.17  0.06  0.00  2.0  2  6.51  0.88  0.06  0.00  2.0  7.30  1.12  0.13  0.00  2.0  3  13.19  1.41  0.15  0.00  2.0  14.44  2.14  0.19  0.00  2.1  4  21.78  2.31  0.16  0.00  2.1  23.52  3.59  0.20  0.00  2.1  5  27.99  4.77  0.14  0.00  2.2  30.54  5.10  0.20  0.00  2.2  6  34.29  6.91  0.30  0.00  2.2  37.10  6.76  0.36  0.00  2.3  7  37.98  9.02  0.46  0.00  2.3  40.00  11.15  0.55  0.00  2.4  8  39.97  11.72  0.56  0.00  2.5  40.86  13.07  0.60  0.00  2.5  9  40.78  13.14  0.65  0.00  2.5  41.26  16.08  1.04  0.00  2.6  10  39.61  14.53  1.00  0.00  2.5  38.04  19.86  1.69  0.00  2.7  11  38.00  16.10  1.20  0.00  2.6  35.42  22.62  2.34  0.01  2.8  12  34.80  18.57  1.68  0.00  2.7  31.86  25.70  3.33  0.00  3.0  13  32.04  20.04  2.26  0.01  2.8  28.68  27.47  4.20  0.00  3.1  14  29.82  21.27  2.78  0.01  2.9  27.33  27.69  5.34  0.00  3.2  15  26.59  22.78  3.05  0.00  3.0  25.23  27.52  5.93  0.00  3.2  16  25.99  23.17  3.57  0.00  3.1  23.78  26.60  6.42  0.03  3.3  17  23.89  21.32  4.20  0.01  3.1  22.32  25.58  7.09  0.03  3.3  18  22.29  21.27  3.79  0.00  3.1  20.21  24.27  7.30  0.00  3.4  19  21.10  21.02  5.17  0.00  3.2  19.13  22.87  8.13  0.02  3.4  ≥20  22.31  22.59  5.79  0.00  3.2  20.78  23.00  8.18  0.07  3.4  Total  22.28  22.65  4.85  0.00  2.7  28.82  17.99  3.17  0.01  2.8  Thyroid cysts were classified into four categories according to maximum diameter (≤3.0, 3.1–5.0, 5.1–20.0, and ≥20.1 mm). View Large Table 3 and Supplemental Fig. 2 show the age- and sex-specific detection rates and multifocality of thyroid nodules. Subjects with thyroid nodules included both subjects with benign and malignant nodules. In total, the detection rates of thyroid nodules were 1.0% and 1.7% in male and female subjects, respectively. There was a significant difference between male and female subjects (P < 0.001). Thyroid cysts were also detected in 48.8% and 52.5% of subjects with thyroid nodules in male and female subjects, respectively. A proportional increment in the detection rate of thyroid nodules with age was observed in either sex (P < 0.0001). An evident sex difference was observed in subjects aged 10 years or older. An age-dependent increase in the detection rate started at age 10 years in female subjects, at which point it reached 1.0%. In male subjects, an apparent increase appeared after the age of 14 years, at which point the detection rate was 1.0%. The group aged 20 years or older exhibited the highest detection rates (3.5% and 6.7% in male and female subjects, respectively). Multifocal nodules were observed in 13.0% and 15.0% of subjects with thyroid nodules in male and female subjects, respectively. The multifocality of nodules was consistently higher than 10% from the age of 7 years in both sexes. Table 3. Detection Rate and Multifocality of Thyroid Nodules According to Sex and Age at Examination Age at Examination (y)  Male Subjects  Female Subjects  n  Detection Rate (%)  Multifocality (%)  n  Detection Rate (%)  Multifocality (%)  0  0  0.0    0  0.0    1  6  0.3  0.0  8  0.5  12.5  2  21  0.4  4.8  10  0.2  0.0  3  12  0.2  0.0  24  0.4  8.3  4  35  0.5  14.3  24  0.4  20.8  5  33  0.5  3.0  20  0.3  5.0  6  39  0.5  2.6  34  0.4  17.6  7  42  0.5  14.3  45  0.5  11.1  8  47  0.5  12.8  58  0.7  15.5  9  46  0.5  15.2  56  0.6  7.1  10  56  0.6  10.7  92  1.0  20.7  11  66  0.7  15.2  110  1.2  13.6  12  75  0.8  16.0  151  1.6  15.9  13  88  0.9  13.6  165  1.8  15.2  14  102  1.0  14.7  170  1.8  14.7  15  109  1.0  11.9  189  2.5  10.1  16  114  1.5  17.5  216  2.8  15.7  17  126  1.7  9.5  274  3.6  13.9  18  159  2.6  11.3  245  3.8  13.9  19  117  2.6  13.7  265  4.8  16.2  ≥20  122  3.5  18.9  299  6.7  19.7  Total  1415  1.0  13.0  2455  1.7  15.0  Age at Examination (y)  Male Subjects  Female Subjects  n  Detection Rate (%)  Multifocality (%)  n  Detection Rate (%)  Multifocality (%)  0  0  0.0    0  0.0    1  6  0.3  0.0  8  0.5  12.5  2  21  0.4  4.8  10  0.2  0.0  3  12  0.2  0.0  24  0.4  8.3  4  35  0.5  14.3  24  0.4  20.8  5  33  0.5  3.0  20  0.3  5.0  6  39  0.5  2.6  34  0.4  17.6  7  42  0.5  14.3  45  0.5  11.1  8  47  0.5  12.8  58  0.7  15.5  9  46  0.5  15.2  56  0.6  7.1  10  56  0.6  10.7  92  1.0  20.7  11  66  0.7  15.2  110  1.2  13.6  12  75  0.8  16.0  151  1.6  15.9  13  88  0.9  13.6  165  1.8  15.2  14  102  1.0  14.7  170  1.8  14.7  15  109  1.0  11.9  189  2.5  10.1  16  114  1.5  17.5  216  2.8  15.7  17  126  1.7  9.5  274  3.6  13.9  18  159  2.6  11.3  245  3.8  13.9  19  117  2.6  13.7  265  4.8  16.2  ≥20  122  3.5  18.9  299  6.7  19.7  Total  1415  1.0  13.0  2455  1.7  15.0  View Large To analyze the detection rates of thyroid nodules within each size range, we classified the nodules into four categories according to each nodule’s maximum diameter (≤5.0, 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm) and divided the subjects into five groups according to age (0 to 4, 5 to 9, 10 to 14, 15 to 19, and ≥20 years) (Table 4). In participants with multiple nodules, the maximum diameter of the largest nodule was subjected to this analysis. Although nodules in the ≤5.0 mm category were predominant in both sexes below the age of 10 years, nodules within 5.1 to 10.0 mm were predominant in the age groups 10 to 14, 15 to 19, and ≥20 years. An age-dependent increase in the detection rate in all size groups in both sexes and obvious increments in all size groups appeared in the age groups of 10 to 14 and 15 to 19 years in female and male subjects, respectively. This difference in the age shifting to an upward trend in male and female subjects resulted in a sex difference in the detection rate in the 10- to 14-year age group and older. In addition, there were age-dependent increases in the median of nodule diameters in both sexes (male: r = 0.316, P < 0.0001; female: r = 0.190, P < 0.0001) in which no sex differences were evident (P > 0.05 for adjusted for age). Table 4. Age- and Sex-Dependent Detection Rate and Median of Thyroid Nodules Age at Examination (y)  Male Subjects  Female Subjects  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  0–4  20,642  0.30  0.05  0.01  0.00  0.36  4.0  19,485  0.26  0.06  0.02  0.00  0.34  3.6  5–9  42,333  0.34  0.10  0.04  0.00  0.49  4.3  40,485  0.34  0.16  0.03  0.00  0.53  4.2  10–14  48,934  0.42  0.30  0.06  0.01  0.79  4.8  46,528  0.61  0.61  0.21  0.05  1.48  5.7  15–19  33,433  0.68  0.87  0.25  0.07  1.87  6.0  35,091  1.17  1.48  0.60  0.14  3.39  6.2  ≥20  3488  1.06  1.83  0.49  0.11  3.50  6.4  4486  2.36  2.81  1.27  0.22  6.67  6.1  Total  148,830  0.45  0.37  0.10  0.02  0.95  5.2  146,075  0.68  0.69  0.26  0.06  1.68  5.8  Age at Examination (y)  Male Subjects  Female Subjects  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  n  ≤5.0 mm (%)  5.1–10.0 mm (%)  10.1–20.0 mm (%)  ≥20.1 mm (%)  Total (%)  Median (mm)  0–4  20,642  0.30  0.05  0.01  0.00  0.36  4.0  19,485  0.26  0.06  0.02  0.00  0.34  3.6  5–9  42,333  0.34  0.10  0.04  0.00  0.49  4.3  40,485  0.34  0.16  0.03  0.00  0.53  4.2  10–14  48,934  0.42  0.30  0.06  0.01  0.79  4.8  46,528  0.61  0.61  0.21  0.05  1.48  5.7  15–19  33,433  0.68  0.87  0.25  0.07  1.87  6.0  35,091  1.17  1.48  0.60  0.14  3.39  6.2  ≥20  3488  1.06  1.83  0.49  0.11  3.50  6.4  4486  2.36  2.81  1.27  0.22  6.67  6.1  Total  148,830  0.45  0.37  0.10  0.02  0.95  5.2  146,075  0.68  0.69  0.26  0.06  1.68  5.8  Thyroid nodules were classified into four categories according to maximum diameter (≤5.0, 5.1–10.0, 10.1–20.0, and ≥20.1 mm). View Large In total, 746 male and 1478 female participants who had nodules ≥5.1 mm or cysts ≥20.1 mm were recommended to have a secondary confirmatory examination. As of March 2016, 91.6% and 91.3% of male and female subjects had undergone this examination, respectively. FNAC was performed in 174 male and 367 female participants whose sonographic findings in precise ultrasound examination met the criteria for performing FNAC (14). In total, 112 cases (38 in male subjects and 74 in female subjects) were cytologically diagnosed as malignancy or suspected malignancy. Table 5 and Supplemental Fig. 3 show the age and sex distribution of the detection rates of thyroid nodules that were cytologically diagnosed as malignancy or suspected malignancy. The adjusted detection rate corrected by the implementation rate of secondary confirmatory examinations is shown in Table 5. This rate was 0 up to the age of 13 years for male subjects and 8 years for female subjects and then showed significant upward trends in male and female subjects (P < 0.0001) that were higher in female subjects than in male subjects (P = 0.0036). Table 5. Age and Sex Distribution of Detection Rates of Thyroid Nodules Cytologically Diagnosed as Malignancy or Suspected Malignancy Age at Examination (y)  Male Subjects  Female Subjects  No.  Detection Rate (%)  Adjusted Rate (%)  n  Detection Rate (%)  Adjusted Rate (%)  0  0  0.000    0  0.000    1  0  0.000    0  0.000  0.000  2  0  0.000  0.000  0  0.000  0.000  3  0  0.000  0.000  0  0.000  0.000  4  0  0.000  0.000  0  0.000  0.000  5  0  0.000  0.000  0  0.000  0.000  6  0  0.000  0.000  0  0.000  0.000  7  0  0.000  0.000  0  0.000  0.000  8  0  0.000  0.000  1  0.012  0.013  9  0  0.000  0.000  0  0.000  0.000  10  0  0.000  0.000  1  0.011  0.012  11  0  0.000  0.000  3  0.032  0.035  12  0  0.000  0.000  2  0.021  0.024  13  4  0.041  0.043  2  0.021  0.023  14  3  0.030  0.032  6  0.063  0.071  15  5  0.064  0.068  8  0.104  0.112  16  3  0.041  0.041  5  0.065  0.071  17  3  0.040  0.042  11  0.143  0.154  18  10  0.165  0.188  9  0.139  0.154  19  7  0.153  0.170  15  0.270  0.299  ≥20  3  0.086  0.106  11  0.245  0.281  Total  38  0.026  0.028  74  0.051  0.056  Age at Examination (y)  Male Subjects  Female Subjects  No.  Detection Rate (%)  Adjusted Rate (%)  n  Detection Rate (%)  Adjusted Rate (%)  0  0  0.000    0  0.000    1  0  0.000    0  0.000  0.000  2  0  0.000  0.000  0  0.000  0.000  3  0  0.000  0.000  0  0.000  0.000  4  0  0.000  0.000  0  0.000  0.000  5  0  0.000  0.000  0  0.000  0.000  6  0  0.000  0.000  0  0.000  0.000  7  0  0.000  0.000  0  0.000  0.000  8  0  0.000  0.000  1  0.012  0.013  9  0  0.000  0.000  0  0.000  0.000  10  0  0.000  0.000  1  0.011  0.012  11  0  0.000  0.000  3  0.032  0.035  12  0  0.000  0.000  2  0.021  0.024  13  4  0.041  0.043  2  0.021  0.023  14  3  0.030  0.032  6  0.063  0.071  15  5  0.064  0.068  8  0.104  0.112  16  3  0.041  0.041  5  0.065  0.071  17  3  0.040  0.042  11  0.143  0.154  18  10  0.165  0.188  9  0.139  0.154  19  7  0.153  0.170  15  0.270  0.299  ≥20  3  0.086  0.106  11  0.245  0.281  Total  38  0.026  0.028  74  0.051  0.056  The adjusted detection rate is the detection rate corrected by the implementation rate of secondary confirmatory examinations. View Large To analyze the detection rate of thyroid nodules that had been cytologically diagnosed as malignancy or suspected malignancy within each size range, we classified the nodules into four categories according to the maximum diameter measured in the secondary confirmatory examination (≤5.0, 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm) (Table 6). There was a limited number of male subjects with thyroid cancer, so we demonstrated the detection rates not according to sex. No malignant nodules ≤5.0 mm were found in any age group because participants with nodules of ≤5.0 mm had not been recommended for the secondary confirmatory examinations or FNAC. There was an age-dependent increase in the adjusted detection rates of malignant nodules in three categories (5.1 to 10.0, 10.1 to 20.0, and ≥20 mm), but that in the 5.1 to 10.0 mm category reached a plateau in the ≥20 group. In addition, there were age-dependent increases in the median of nodule diameters (r = 0.246, P < 0.0001). Table 6. Detection Rate of Classified by Size Categories and Median Diameter of Thyroid Nodules Cytologically Diagnosed as Malignancy or Suspected Malignancy Age at Examination (y)  Detection Rate (%)  Adjusted Detection Rate (%)  Median (mm)  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  0–4  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000    5–9  0.000  0.000  0.001  0.000  0.001  0.000  0.000  0.001  0.000  0.001  12.0  10–14  0.000  0.005  0.013  0.004  0.022  0.000  0.006  0.014  0.005  0.024  12.3  15–19  0.000  0.045  0.050  0.016  0.111  0.000  0.049  0.054  0.017  0.121  11.5  ≥20  0.000  0.038  0.088  0.050  0.176  0.000  0.044  0.103  0.059  0.206  14.9  Total  0.000  0.013  0.018  0.006  0.038  0.000  0.014  0.020  0.007  0.042  12.4  Age at Examination (y)  Detection Rate (%)  Adjusted Detection Rate (%)  Median (mm)  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  ≤5.0 mm  5.1–10.0 mm  10.1–20.0 mm  ≥20.1 mm  Total  0–4  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000  0.000    5–9  0.000  0.000  0.001  0.000  0.001  0.000  0.000  0.001  0.000  0.001  12.0  10–14  0.000  0.005  0.013  0.004  0.022  0.000  0.006  0.014  0.005  0.024  12.3  15–19  0.000  0.045  0.050  0.016  0.111  0.000  0.049  0.054  0.017  0.121  11.5  ≥20  0.000  0.038  0.088  0.050  0.176  0.000  0.044  0.103  0.059  0.206  14.9  Total  0.000  0.013  0.018  0.006  0.038  0.000  0.014  0.020  0.007  0.042  12.4  The adjusted detection rate is the detection rate corrected by the implementation rate of secondary confirmatory examinations. Thyroid nodules were classified into four categories according to maximum diameter (≤5.0, 5.1–10.0, 10.1–20.0, and ≥20.1 mm). View Large Nodules cytologically diagnosed as malignancy or suspected malignancy within 10.1 to 20.0 mm were predominant in the age groups of 10 to 14, 15 to 19, and ≥20 years. However, these detection rates were influenced by the implementation criteria for FNAC (12, 14). The proportions of the estimated number of subjects with nodules cytologically diagnosed as malignancy or suspected malignancy to the number of subjects with nodules were 2.7%, 11.0%, and 17.8% in the categories of 5.1 to 10.0, 10.1 to 20.0, and ≥20.1 mm, respectively. Discussion We report the detailed age and sex distribution of findings from TUEs among children and adolescents, which were conducted as the first-round examination of the FHMS within 3 years of the Fukushima nuclear power plant accident. The examination results varied substantially by age group. A thyroid colloid cyst is a common benign thyroid lesion showing marked follicular dilatation and epithelial flattening (15). In our study, the mixed solid-cystic type tumor, which is a cyst with a solid component, was not classified as a cyst; instead, it was classified as a nodule because this mixed-type tumor sometimes occurs in thyroid cancer. Therefore, most of thyroid cysts in this study had no pathological significance. Few reports have studied the prevalence of thyroid cysts in children and adolescents. In the area surrounding Chernobyl, ultrasound examination of thyroid glands revealed that 502 of the 120,605 children examined had cystic lesions, a prevalence rate of only 0.42% (16). Technical advances in ultrasound equipment have led to the detection of small nodules and cysts and to an increase in prevalence rates. Avula et al. (17) conducted a retrospective analysis of clinical and ultrasound findings in 287 Canadian children aged 0 to 17 years between 2006 and 2007 and detected incidental thyroid findings in 52 children (18%). Among these incidental thyroid findings, 35 were small (<4 mm), well-defined cysts, and the prevalence rate was 12%. The Investigation Committee for the Proportion of Thyroid Ultrasound Findings in Japan Association of Breast and Thyroid Sonology studied the prevalence rate of thyroid nodular lesions detected using high-resolution sonography in a general population of Japanese children living in three prefectures located far from Fukushima (9, 10). The subjects of that study were children and adolescents aged between 3 and 18 years, and it was revealed that the prevalence rate of thyroid cysts was 56.5%, which appears to be higher than that of the current study. The bias in subjects’ age in the three-prefecture study might account for the difference in the prevalence rate; no children aged 0 to 2 years, and only a small number of children aged 3 to 5 years, were recruited (9). As shown in the current study, children aged 0 to 5 years exhibited a relatively low prevalence rate. The proportion of participants who had cysts of ≤3.0 mm increased from age 0 to 10 years and decreased thereafter until the age of 20 years, whereas the proportion of those who had cysts of 3.1 to 5.0 and 5.1 to 20.0 mm, as well as the median size of cysts, increased with age. These findings may imply that some cysts that are ≤3.0 mm may regress and disappear within a short period, but this is not the case with larger cysts. In contrast, the detection rate of thyroid nodules in all size categories showed an age-dependent increase. Thyroid nodules are common in adult patients but not in children or adolescents. Numerous studies suggest that the prevalence of thyroid nodules largely depends on the method of examination, with a prevalence of 2% to 6% with palpation, 19% to 35% with ultrasound, and 8% to 65% in autopsy data (18). In contrast to adults, much less is known about the prevalence of thyroid nodules in the general population of children. Rallison et al. (19) examined 5179 school children in Utah, Nevada, and Arizona for thyroid abnormalities because of possible exposure to radiation from fallout. Palpation of the thyroid gland found nodularity of the thyroid in 98 (1.8%) subjects. In addition, a retrospective study using ultrasound was reported by Avula et al. (17). Of 287 children, 9 (3.1%) had hypoechoic solid nodules with smooth straight margins and tiny hyperechoic foci, which were considered to be intrathyroid ectopic thymus. Three nodules (1.0%), two (0.7%) of which had target-like findings suggesting cystic nodules and one (0.3%) of which was an isoechoic well-defined nodule, were found. In another study, Aghini-Lombardi et al. (20) also reported that thyroid nodular goiter was found in 0.5% of children (1 to 14 years old) and in 2.1% of adolescents and young adults aged 15 to 25 years. The Investigation Committee for the Proportion of Thyroid Ultrasound Findings revealed that the prevalence of thyroid nodules in Japanese children between 3 and 18 years was 1.6%, and the age-adjusted prevalence of thyroid nodules was 1.54% (9, 10). These results are quite similar to the outcomes from the TUE in Fukushima presented in the current study, in which the detection rates of thyroid nodules were 1.0% and 1.7% in male and female subjects, respectively. Similar age dependency regarding the prevalence of thyroid cysts and nodules to that in this study was shown in a study by The Investigation Committee for the Proportion of Thyroid Ultrasound Findings, in which TUE for children was conducted using the same procedure used in the current study in three Japanese prefectures (Aomori, Yamanashi, and Nagasaki) (9, 10). The proportions of those with cysts in the age groups 3 to 4, 5 to 9, 10 to 14, and 15 to 18 years in that study were 19.7%, 49.1%, 60.5%, and 59.5%, respectively, for male and female subjects combined (10). The corresponding proportions in the current study are similar: 20.8%, 47.9%, 57.5%, and 53.2%, respectively. The proportions of those with nodules in the age groups of 3 to 4, 5 to 9, 10 to 14, and 15 to 18 years were 1.41%, 0.64%, 1.50%, and 2.69%, respectively, for male and female subjects combined (10). In the age group of 3 to 4 years, there was a lack of reliability in the detection rate because only one subject with malignancy or suspected malignancy was found in this group. The corresponding proportions for the same age groups in the current study were also similar (0.36%, 0.51%, 1.13%, and 2.45%, respectively). In the current study, the detection rates of thyroid cysts and nodules in female subjects were higher than those in male subjects. However, the difference between sexes in the prevalence of cysts was clearly smaller than that of thyroid nodules. A similar tendency in sex difference in the prevalence of thyroid cysts and nodules has been shown in previous reports (9, 10). Hayashida et al. (10) reported that the prevalence of thyroid cysts and nodules in male and female subjects was 53.4% to 60.0% and 1.20% to 2.05%, respectively. In addition, the current study showed a sex difference in the detection rate of nodules in participants aged 10 years or older. That the age of 10 years in female subjects almost coincides with the onset of puberty suggests that the sex difference during puberty might be induced by estrogen-dependent stimulation of thyroid cell proliferation (21). Thyroid cancer in the youngest age group among this baseline survey was detected only in subjects aged 13 years for male subjects and 8 years for female subjects. The adjusted detection rate increased with age and was higher in female subjects than in male subjects. A difference between the sexes was evident after the age of 14 years, and the overall adjusted detection rate of thyroid cancer was 0.028% and 0.056% in male and female subjects, respectively. Few reports studying the prevalence of thyroid cancer in children and adolescents are available. Screening of thyroid disease by palpation revealed thyroid cancer in 2 of 5179 school children aged 11 to 18 years in Utah, Nevada, and Arizona (19). In that study, the prevalence rate of thyroid cancer was 0.04%. A Ukraine–US cohort study conducted after the Chernobyl accident reported that the detection of thyroid cancer during the first screening from 1998 to 2000 was 0.149% in the control group (<200 mSv dose category) by palpation and/or ultrasound targeting subjects aged 12 to 33 years (average, 24.7 years) (22). A Belarus–US cohort study after the Chernobyl disaster has also shown that the detection of thyroid cancer during the first screening from 1996 to 2001 was 0.301% in the control group (<50-mSv dose category) by palpation or ultrasound, targeting subjects aged 10 to 33 years (23). The Investigation Committee for the Proportion of Thyroid Ultrasound Findings in Japan performed a secondary confirmatory examination study for subjects with nodules ≥5.1 mm or cysts ≥20.1 mm selected from the cohort of 4365 children aged 3 to 18 years (11). In total, 31 of 44 children with nodules ≥5.1 mm or cysts ≥20.1 mm agreed to be enrolled in this study, and one subject was diagnosed with papillary thyroid carcinoma (11). These findings suggest that the adjusted detection rate corrected by the implementation rate of secondary confirmatory examinations was 0.03%. An age-dependent increase in the incidence of thyroid cancer has been reported by the national cancer registry in Japan and the United States (24, 25) and in the number of childhood patients with thyroid carcinoma in single institutions (26, 27). In contrast, the incidence of pediatric thyroid cancer in the Republic of Belarus after the Chernobyl disaster was shown to be higher in the younger population. The highest number of patients that subsequently developed thyroid cancer was in the age group of younger than 1 year at the time of the accident. A study of A-bomb survivors exposed in childhood reported that not only thyroid cancer but also benign nodules and cysts were associated with thyroid radiation dose (28). Although the sensitivity and quality control of diagnostic criteria should be carefully considered in addition to other confounding factors on thyroid carcinogenesis, it is important to observe the frequency of thyroid benign nodules and cysts when investigating the association between radiation exposure and thyroid cancer in childhood. There were some limitations to this study. First, the findings may not be completely comparable to other populations with a different diet/environment and different ethnicity. For example, the prevalence of thyroid nodules depends on the amount of iodine intake. It was reported that even small changes in iodine intake from mandatory iodination of table and bread salt significantly influence goiter prevalence, nodule incidence, and thyroid dysfunction and raise the risk of thyroid nodules (18). Residents of Japan have high iodine intake associated with frequent consumption of seaweed (29). Second, we could not record the distribution of the number of lesions in the cases with multiple lesions because we had to perform ultrasound examinations for the large number of young residents with a limited number of examiners within 2.5 years. In addition, some subjects with multiple cysts showed many small colloid cysts. Finally, this study had no control cohort with a similar number of subjects. The Chernobyl nuclear accident occurred in 1986, and the incidence of childhood thyroid cancer in Belarus has exhibited an elevation since 1990 (30). Thus, the expected latency for radiation-induced thyroid cancer is considered to be 4 to 5 years (14). In the current study, the fact that the examination period was within 3 years after the nuclear accident suggests that this study was performed before any radiation-induced influence. Additionally, a study with a small number of subjects residing in other regions of Japan reported reference data (9, 10). This study showed similar prevalence rates of thyroid cysts and nodules. In summary, the accurate prevalence of the findings of thyroid abnormalities and information on age dependence in neonates to adolescents has been clarified in Fukushima following the introduction of a highly sophisticated methodology that can easily detect small and asymptomatic thyroid abnormalities. Because the mechanisms of occurrence and growth of thyroid cancer, nodules, and cysts in children and adolescents have not been not sufficiently analyzed, further long-term follow-up of ultrasound examination is a key issue, including the results from the second and future rounds of examination, which was started in April 2014. Abbreviations: FHMS Fukushima Health Management Survey FNAC fine-needle aspiration cytology TUE thyroid ultrasound examination. Acknowledgments Other participating expert committee members, advisors, and staff members in the Fukushima Health Management Survey: Kenji Kamiya, Kenneth E. Nollet, Kumiko Tsuboi, Shiro Matsui, Seisho Tanaka, Masaharu Maeda, Shigeatsu Hashimoto, Keiya Fujimori, Suguru Ishida, Testuo Ishikawa, Akira, Sakai, Yuko Hino, Hiroshi Mizunuma, Keiichi Nakano, Satoshi Suzuki, Chiyo Ohkouchi, Tomomi Hakoiwa, Chisato Takahashi, Yukari Sato, Ayako Sato, Nobuko Sakuma, Toshie Sakagami, Manabu Ohishi, Norikazu Abe, Masahiko Henmi, Yukie Yamaya, Takao Yamahata, Yukiko Horikoshi, Yoko Nihei, Risa Ujiie, Sakiko Meguro, Ayana Okazaki, Yumiko Kurozu, Mizuki Sekino, Yuko Sato, and Yayoi Sato. The authors thank the staff of the Fukushima Health Management Survey for their important contributions. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Fukushima prefectural government. Financial Support: This work was supported by the National Health Fund for Children and Adults Affected by the Nuclear Incident for the design and conduct of the study. 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Published: Mar 1, 2018

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