Prevalence of Ectopic Intrathyroidal Thymus in Japan: The Fukushima Health Management Survey

Introduction

Ectopic thymus can be located anywhere along the developmental pathway of thymic descent through the neck to the upper mediastinum (1 –4). Although ectopic intrathyroidal thymus has recently been reported in children, it is thought to be uncommon and can be misdiagnosed as a thyroid tumor, resulting in unnecessary surgery (5 –11). To date, few reports have studied the prevalence of ectopic intrathyroidal thymus on a large scale.

After the disaster at the Fukushima Daiichi Nuclear Power Plant following the Great East Japan Earthquake in 2011, Fukushima Prefecture started to perform the Fukushima Health Management Survey, including thyroid examination using ultrasound (US), as the disaster at Chernobyl, Ukraine, in 1986 revealed a significant increase in radiation-induced thyroid cancer. During the present examination, cases with ectopic intrathyroidal thymus were detected. However, a large-scale evaluation of ectopic intrathyroidal thymus cases was not performed. Although the current study was conducted solely based on ultrasonographic appearance, herein, the updated prevalence of ectopic intrathyroidal thymus in the Fukushima Study is provided.

Methods and Subjects

Results

Of the 37,816 participants, 375 cases (0.99%) of ectopic intrathyroidal thymus were found (211 boys; M _age=7.0 years; Table 1). The intrathyroidal thymus was located in the right (n=180), left (n=178), or bilateral (n=17) thyroid lobes.

On ultrasonography, typical findings of ectopic intrathyroidal thymus appeared as an irregular, triangular, polygonal hypoechoic or hyperechoic area, with punctate, granular, linear echogenic foci (Fig. 1).

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FIG. 1.

An intrathyroidal ectopic thymus in an eight-year-old girl. Transverse (A) and longitudinal (B) sonograms show a well-defined polygonal hypoechoic lesion (arrows) in the right middle portion of the thyroid with granular echogenic foci.

Table 1 shows characteristics of participants with and without ectopic intrathyroidal thymus. The prevalence was significantly associated with age (p<0.001). The ages of the participants with intrathyroidal thymus were significantly lower than those without. The subjects were divided into four groups depending on the age at the time of survey: 0–4 years, 5–9 years, 10–14 years, and 15–19 years. The prevalence of intrathyroidal thymus was inversely associated with age. The prevalence in females was significantly lower than that in males. The mean levels of BMI in the participants with intrathyroidal thymus were significantly lower than those without in the 5–9 and 10–14 age groups, but not in the 0–4 and 15–19 age groups. The prevalence of obesity tended to be lower in the participants with intrathyroidal thymus than those without, but it did not reach statistically significance (p=0.11).

As shown in Table 2, logistic analysis showed that the factors of age, sex, and BMI were independently associated with the prevalence of ectopic intrathyroidal thymus in the subjects studied. Further, obesity tended to be associated with lower prevalence of intrathyroidal thymus after adjusting for age and sex (OR=0.71 [CI 0.48–1.05], p=0.09). For more precise analyses, logistic analysis was performed in each age group. In the 0–4 age group, there was an independent positive relationship between age and prevalence of intrathyroidal thymus. In the 10–14 age group, girls (OR=0.46 [CI 0.27–0.78], p=0.004) had higher odds of decreasing prevalence of ectopic intrathyroidal thymus. In addition, higher BMI (OR=0.90 [CI 0.83–0.98], p=0.02) was associated with a lower prevalence (Table 2). There were no significant correlations with age, sex, or BMI in the 5–9 or 15–19 age groups. However, in the 5–9 age group, obesity was associated with a lower prevalence of intrathyroidal thymus after adjusting for age and sex (OR=0.44 [CI 0.22–0.90], p=0.02).

Discussion

The thymus is derived from the third and fourth pharyngeal pouches, and during the eighth week of gestation, the primordial thymic tissue migrates from the pharynx to the anterior mediastinum. The thymus undergoes a process called involution, which is defined as a decrease in the size and weight of the gland with advancing age. This process starts at puberty, when the thymus is at its maximum absolute weight. During involution, the epithelial component atrophies, resulting in scattered small lymphocytes in abundant adipose tissue (14). Eventually, thymic remnants can be located anywhere along the developmental pathway of thymic descent, including inside the thyroid (15 –17). Ectopic intrathyroidal thymus has been previously reported as an incidental finding. In 1937, Gilmour described thymus entirely within the thyroid capsule (18). Ectopic intrathyroidal thymus is thought to be a rare entity and is occasionally detected during thyroid ultrasonography in children (19,20). The prevalence of ectopic intrathyroidal thymus has been reported in 0.4–3.14% of the patients who had medical or surgical reasons to undergo US examination (20,21). In an autopsy study, ectopic intrathyroidal thymus was found in 5.1% of children (10), although the sample size was small (n=58). In the present study, 375 (0.99%) cases with ectopic intrathyroidal thymus were observed. To the authors' knowledge, this is the first report on the prevalence of ectopic intrathyroidal thymus using ultrasonography in a large general population.

In a recent review, thymic involution was described as being the result of high levels of circulating sex hormones, in particular during puberty (22). Both excessive caloric intake and obesity are proven factors that accelerate thymic involution.

In the present study, the prevalence of ectopic intrathyroidal thymus was inversely associated with age and BMI for all subjects. However, age increased the odds for the prevalence of intrathyroidal thymus in the 0–4 age group, indicating that thymus may be developing rather than involuting during infancy as previously described (23). Among all groups studied, a sex- and BMI-dependent alteration was observed in the 10–14 age group. Either obesity or female sex was an independent factor for the decreasing prevalence of intrathyroidal thymus in this age group.

The prevalence of intrathyroidal thymus using US is affected by accurate visualization. As an intrathyroidal thymus is more easily detected in slim subjects by US, it is possible that the association between thymic involution and lower BMI could be the result of more accurate visualization of the thyroid in slim participants. The significant influence of the BMI was, however, only observed in the 10–14 age group, indicating that a specific developmental period may be present in terms of involution of intrathyroidal thymus, rather than the possibility that BMI itself affects the visualization of thymus tissue.

Currently, involution of the thymus has not been well described in humans, although thymic involution has been precisely investigated in vertebrates, especially in rodents (22,23). Sex- and BMI-related thymic involution has been clinically shown in this study.

Although the differential diagnosis between intrathyroidal thymus and thyroid tissue is sometimes difficult based on thyroid US examination, ectopic intrathyroidal thymus typically appears as an irregular, triangular, polygonal hypoechoic or hyperechoic area with punctate, granular, linear echogenic foci surrounded by normal thyroid tissues (24,25). Because thyroid cancer is seen with increased incidence in the 10–19 age group, special care should be taken when assessing these patients (26). There have been some reports on patients who underwent thyroid lobectomy because the ectopic thymus mimicked a thyroid nodule. Thus, when evaluating US findings of the thyroid gland in children, careful observation is necessary to exclude the possibility of intrathyroidal thymus. In the Fukushima Health Management Survey, participants who had a thyroid nodule ≥5.1 mm underwent detailed examination involving a precise, high-resolution US examination. There were 185 participants who had thyroid nodules ≥5.1 mm in the present study. Of these participants, one participant and 12 participants were reclassified by detailed examination including a fine-needle aspiration cytology as having ectopic intrathyroidal thymus and papillary thyroid cancer respectively. Twelve participants who were found to have a papillary thyroid cancer by fine-needle aspiration cytology underwent thyroid surgery; the histological diagnosis confirmed papillary thyroid cancer in all cases, and none had intrathyroidal thymus tissue. A limitation of the present study is that the thymic tissues found in the children based on US criteria we were not cytologically confirmed, and the possibility cannot be ruled out that some of the thymic tissues were in fact thyroid nodules. However, based on the US characteristics, these lesions can be safely monitored by biannual thyroid US examination of the Fukushima Health Management Survey.

In conclusion, the prevalence of ectopic intrathyroidal thymus was 0.99% in the Fukushima Study. The prevalence was significantly inversely associated with age. Further longitudinal evaluation should be conducted.