Graves' Disease Diagnosed during an Evaluation of an Abnormal Opacity on a Chest X-ray with a Review of the Pertinent Literature

Abstract

We treated a 43-year-old woman with Graves' disease (GD), complicated by thymic hyperplasia. Routine chest radiography revealed an abnormal opacity, and computed tomography revealed an anterior mediastinal tumor. At the initial visit to our institution, blood tests revealed hyperthyroidism with positive thyroid-stimulating hormone receptor antibodies, confirming the diagnosis of GD. As the patient opted for long-term antithyroid drug therapy, radioiodine therapy was administered. A computed tomography-guided biopsy revealed thymic hyperplasia. Following radioiodine therapy, the thyroid function normalized, and the tumor significantly shrank. Based on the pathology and clinical course, the patient was diagnosed with thymic hyperplasia secondary to GD, which regressed with conservative management.

Introduction

Graves' disease (GD), a well-recognized autoimmune disorder, is characterized by the persistent stimulation of the thyroid gland by autoantibodies (TRAb) targeting the thyroid-stimulating hormone (TSH) receptor. This pathological stimulation results in the excessive production of thyroid hormones, which manifests clinically as hyperthyroidism. The key symptoms include weight loss, tachycardia, hyperhidrosis, exophthalmos, and finger tremors. Although GD predominantly affects young to middle-aged women, its pathogenesis involves a systemic autoimmune reaction that may extend to extrathyroidal organs (1).

Although thymic hyperplasia associated with GD has been reported in several cases, it remains relatively underrecognized in clinical practice (2). The thymus is a vital organ that is responsible for the differentiation and maturation of T lymphocytes in the immune system. Under normal conditions, the thymus undergoes involution with age; however, hyperplasia can occur in autoimmune diseases (3). Clinically, thymic hyperplasia is typically asymptomatic and it is most often discovered incidentally through imaging modalities such as chest radiography or computed tomography (CT), which reveal thymic enlargement. When this occurs, differentiation from other mediastinal masses, particularly thymomas and malignant lymphomas, becomes critical, because these conditions require distinct diagnostic and therapeutic pathways. The pathological assessment of thymic lesions plays a pivotal role in this process, as the distinction between benign and malignant findings provides essential information for the accurate diagnosis and formulation of an appropriate treatment strategy. In cases where thymic hyperplasia is associated with GD, normalization of the thyroid function through appropriate medical management can lead to a reduction in thymic size (3).

This case report describes a patient with GD who exhibited minimal subjective symptoms but was found to have an abnormal mediastinal opacity during a routine chest radiographic examination conducted during health screening. Subsequent diagnostic evaluations confirmed the GD diagnosis. Imaging studies and pathological assessments strongly suggested that mediastinal abnormalities were consistent with thymic hyperplasia. Based on these findings, the patient was prioritized to undergo treatment for GD, leading to a normalization of the thyroid function and a significant regression of the thymic lesion. The clinical course and imaging evidence support the conclusion that the mediastinal lesion represented thymic hyperplasia secondary to GD.

Case Report

A 43-year-old woman presented to our hospital with an anterior mediastinal tumor for evaluation and treatment. During routine chest radiography performed four months prior to the initial visit to our institution as part of a health screening, an abnormal mediastinal shadow was identified (Fig. 1). Subsequently, she consulted a nearby respiratory surgery clinic where CT confirmed the presence of an anterior mediastinal tumor (Fig. 2A-C). She visited our institution for a detailed evaluation of an anterior mediastinal tumor. At the initial consultation, laboratory tests revealed thyrotoxicosis, with levels of free Thyroxine (FT4) at 3.44 ng/dL (normal range, 0.70-1.48 ng/dL; FT4; Abbott Japan, Tokyo, Japan), free Tri-iodothyronine (FT3) above the detection limit [＞20.0 pg/mL (normal range, 1.88-3.18 pg/mL; FT3; Abbott Japan, Tokyo, Japan)], and thyroid-stimulating hormone (TSH) below the detection limit [＜0.01 μU/mL (normal range, 0.35-4.94 μU/mL; ARCHITECT TSH; Abbott Japan, Tokyo, Japan)] (Table). Despite these abnormalities, no subjective symptoms of thyrotoxicosis were observed.

Figure 1.

A chest radiograph taken during routine health screening four months prior to the initial visit to our institution. The yellow arrowheads indicate abnormal opacities.

Figure 2.

Computed tomography (CT) was performed during the initial visit to our institution. Yellow arrowheads indicate the thymus. A: axial, B: coronal, C: sagittal.

Table.

Urinalysis, Blood Counts, Biochemistry, Thyroid-related Items, and Tumor Markers in the Patient.

Urinalysis		Biochemistry		Glucose (mg/dL)	114 (73-109)
Specific gravity	1.021	TP (g/dL)	6.9 (6.6-8.1)	HbA1c (%)	6.0 (4.9-6.0)
Protein	-	Albumin (g/dL)	3.9 (4.1-5.1)
Glucose	-	AST (U/L)	25 (13-30)	Thyroid-related items
Hb	-	ALT (U/L)	49 (7-23)	TSH (μIU/mL)	<0.01 (0.35-4.94)
Ketone	-	LDH (U/L)	175 (124-222)	Free T4 (ng/dL)	3.44 (0.70-1.48)
		ALP (U/L)	186 (38-113)	Free T3 (pg/mL)	>20.00 (1.88-3.18)
Blood counts		γ-GTP (U/L)	45 (9-32)	TRAb (IU/L)	3.9 (<1.0)
WBC (×103/μL)	5.5 (3.3-8.6)	Creatinine (mg/dL)	0.37 (0.46-0.79)	TgAb (IU/mL)	851.0 (<28.0)
RBC (×106/μL)	4.59 (3.86-4.92)	Uric acid (mg/dL)	4.8 (2.6-5.5)	TPOAb (IU/mL)	59.8 (<16)
Hb (g/dL)	10.7 (11.6-14.8)	Na (mEq/L)	139 (138-145)	Tg (ng/mL)	1.82 (<37.70)
Ht (%)	33.4 (35.1-44.4)	K (mEq/L)	4.6 (3.6-4.8)
MCV (fL)	72.8 (83.6-98.2)	Cl (mEq/L)	107 (101-108)	Tumor markers
Platelet (×104/μL)	28.9 (15.8-34.8)	Ca (mg/dL)	9.4 (8.8-10.1)	sIL-2R (U/mL)	1,600 (121-613)
		IP (mg/dL)	4.4 (2.7-4.6)	AFP (ng/mL)	12.2 (<7.0)
		LDL-C (mg/dL)	67 (65-163)	CEA (ng/mL)	0.6 (<3.4)
		Triglyceride (mg/dL)	76 (30-117)	CYFRA (ng/mL)	1.4 (<3.5)
		HDL-C (mg/dL)	81 (48-103)	ProGRP (pg/mL)	29.6 (<81.0)

Hb: hemoglobin, WBC: white blood cell, RBC: red blood cell, Ht: hematocrit, MCV: mean corpuscular volume, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transpeptidase, IP: inorganic phosphorus, LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, HbA1C: hemoglobin A1C, TSH: thyroid-stimulating hormone, T₄: thyroxine, T₃: triiodothyronine, TRAb: thyrotropin receptor antibody, TgAb: thyroglobulin antibody, TPOAb: thyroid peroxidase antibody, Tg: thyroglobulin, sIL-2R: soluble interleukin-2 receptor, AFP: alpha-fetoprotein, CEA: carcinoembryonic antigen, CYFRA: cytokeratin fragment 21-1, ProGRP: pro-gastrin-releasing peptide

Physical examination revealed a height of 167 cm, weight of 61 kg, body temperature of 37.0°C; blood pressure of 127/81 mmHg, and pulse rate of 112 bpm. Fine tremors of the hands were observed; however, exophthalmos were absent. The superficial lymph nodes in the cervical and supraclavicular regions were nonpalpable. The conjunctiva showed no signs of anemia or jaundice, and auscultation revealed no abnormalities in the heart or lung sounds. Blood tests indicated mild elevations in alanine aminotransferase (ALT) and gamma-glutamyl transferase levels. Endocrinological and immunological evaluations revealed elevated FT3 and FT4 levels and suppressed TSH levels. The test for anti-TSH receptor antibody (TRAb) returned positive results [TRAb 3.9 IU/L (normal range, ＜1.0 IU/L; DYNOtest TRAb human assay, Yamasa, Tokyo, Japan)]. Electrocardiography revealed sinus tachycardia.

Thyroid ultrasonography demonstrated diffuse glandular enlargement and technetium scintigraphy (^99mTc-pertechnetate) revealed an increased diffuse uptake (13.8%) throughout the thyroid gland (Fig. 3A). One month after the initial visit to our institution, Doppler ultrasonography confirmed an increased vascular flow in the thyroid gland (Fig. 3B). Based on the clinical, imaging, and laboratory findings, the patient was diagnosed with GD.

Figure 3.

A: Technetium scintigraphy (^99mTc-pertechnetate) performed at the initial visit to our institution. B: Neck ultrasound taken one month after the initial visit.

Computed tomography (CT) revealed thymic enlargement with a homogeneous internal structure, and positron emission tomography-CT demonstrated mild, a uniform uptake (SUVmax=3.3) (Fig. 4A). Among the tumor markers evaluated for potential thymic malignancy, the soluble interleukin-2 receptor (sIL-2R) level was markedly elevated at 1,600 U/mL (normal range, 121-613 ng/mL; STACIA CLEIA IL-2R, PHC Holdings, Tokyo, Japan), whereas the alpha-fetoprotein (AFP) level was mildly elevated at 12.2 ng/mL (normal range, ＜7.0 ng/mL; Eclusys AFPII; Roche, Basel, Switzerland). The levels of other tumor markers, including carcinoembryonic antigen (CEA, 0.6 ng/mL; normal range, ＜3.4 ng/mL; Eclusys CEAII; Roche), cytokeratin 19 fragment [CYFRA, 1.4 ng/mL (normal range, ＜3.5 ng/mL; Eclusys CYFRA 21-1; Roche)], and pro-gastrin-releasing peptide (ProGRP, 29.6 pg/mL [normal range, ＜81.0 pg/mL; Lumipulse ProGRP, Fujirebio, Tokyo, Japan]), were within the normal limits. A CT-guided biopsy was performed one month after the initiation of methimazole therapy when the thyroid hormone levels had improved to within the reference range. A histopathological examination revealed densely packed small lymphocytes without any evidence of malignancy, which was consistent with thymic hyperplasia (Fig. 4B, C). Tests for anti-acetylcholine receptor antibodies yielded negative results. Therefore, thymic enlargement was attributed to thymic hyperplasia associated with GD, and a decision was made to prioritize the management of GD. As the patient declined prolonged antithyroid medication therapy and surgery, radioiodine (¹³¹I) therapy was selected as the preferred treatment for GD. Two months after the initial visit to our institution, radioiodine therapy was administered with methimazole used as a bridging therapy, both before and after treatment. Five months after the initial visit to our institution, methimazole administration was discontinued and levothyroxine replacement therapy was initiated. Subsequent thyroid function tests revealed stable hormone levels that were within the reference range.

Figure 4.

A: Positron emission tomography-computed tomography performed one month after the initial visit. B, C: A computed tomography-guided biopsy taken one month after the initial visit. Original magnification: B ×100 and C ×200.

The sIL-2R level, initially elevated at 1,600 U/mL, showed a progressive decline, dropping to 776 U/mL one month after the initial visit to our institution. Four months after the initial visit, the level decreased to 155 U/mL, reaching the reference range. Additionally, CT performed seven months after the initial visit to our institution demonstrated a reduction in the thymic size, with a corresponding sIL-2R level of 216 U/mL. A follow-up CT scan conducted 15 months after the initial visit confirmed complete regression of thymic enlargement, consistent with remission (the sIL-2R level was not measured at that time) (Fig. 5). Based on the clinical course, imaging findings, and normalization of sIL-2R levels, the anterior mediastinal lesion was determined to be thymic hyperplasia associated with GD.

Figure 5.

Clinical course of Graves’ and thymus changes. Yellow arrowheads indicate the thymus. T4: thyroxine, T3: triiodothyronine, TSH: thyroid-stimulating hormone, sIL-2R: soluble interleukin-2 receptor. The date of the initial visit to our institution was December X (X/12).

Discussion

During a routine health check, an abnormal opacity was detected on a chest radiograph, prompting further evaluation. Through detailed examination, the patient was ultimately diagnosed with GD. This case highlights the importance of considering underlying endocrine disorders while interpreting incidental radiographic findings. The abnormal opacity on the chest radiograph was further evaluated using CT, which led to the diagnosis of an anterior mediastinal tumor. A histopathological examination of the lesion by CT-guided biopsy revealed no evidence of malignancy. Given the coexistence of GD, an anterior mediastinal tumor was strongly suspected to represent thymic hyperplasia associated with GD. This condition is well documented to regress with appropriate treatment for GD (3). Consequently, GD management was prioritized. Radioactive iodine therapy (¹³¹I) successfully normalized thyroid function, which was accompanied by significant regression of the anterior mediastinal tumor. Based on the clinical course, the tumor was diagnosed as thymic hyperplasia associated with GD.

Thymic hyperplasia is broadly classified into two types: true thymic hyperplasia (TTH) and follicular thymic hyperplasia (FTH) (4). Although FTH is associated with other autoimmune diseases, including myasthenia gravis (MG), systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, pemphigus, polymyositis, and Addison's disease (3,5,6), GD is associated with both TTH and FTH (7). The histopathological characteristics of FTH include an increase in lymphoid follicles, a marked expansion of the cortical region of the thymus, increased number and altered morphology of Hassall's corpuscles, proliferation of lymphocytes predominantly consisting of T cells, and increased connective tissue (4). In contrast, TTH is characterized by hypertrophied glandular structures composed of cortical and medullary components with fewer distinct histological features (5,7). In the present case, the pathological findings from the CT-guided biopsy revealed no evidence suggestive of malignancies, such as lymphoma. Although cortical thickening and an increased number of small lymphocytes were observed, no other specific features of FTH were noted. Consequently, we were unable to definitively distinguish between TTH and FTH. Nevertheless, thymic hyperplasia was strongly suspected on the basis of the overall findings.

Thymic hyperplasia associated with GD was first described in 1914 (8), and numerous subsequent studies have explored this relationship (9). A study examining the prevalence of thymic hyperplasia among 264 cases of thyrotoxicosis revealed that 16.4% (20/122) of patients with GD exhibited thymic hyperplasia, compared to only 1.4% (2/142) of patients with other causes of thyrotoxicosis, thus indicating a significantly higher prevalence in the former group (10). Despite these findings, the clinical recognition of the association between GD and thymic hyperplasia remains limited (3). This is likely attributable to two main factors: the inconsistent use of thoracic imaging in patients with hyperthyroidism, and insufficient awareness of the potential link between GD and thymic hyperplasia among clinicians.

In the present case, the patient demonstrated clinical signs of thyrotoxicosis, including tachycardia and hand tremors, during examination. Her body temperature was 37.0°C, which was within the normal range. However, these symptoms were not self-reported by the patient and hyperthyroidism was incidentally identified through blood tests at the initial consultation. Furthermore, no findings suggestive of thyrotoxicosis were noted in a health checkup conducted four months prior to the patient's visit to our institution. Notably, previous reports have described cases in which preoperative thyroid function was not assessed, leading to severe complications such as thyroid storm following thymectomy (11). These findings underscore the critical importance of considering hyperthyroidism in the differential diagnosis of patients with thymic tumors. A distinguishing feature of this case was its unique diagnostic sequence. Although most reported cases of thymic hyperplasia associated with GD involve the identification of thymic hyperplasia after the diagnosis of GD, this case presented an atypical clinical course, in which the detection of an anterior mediastinal tumor prompted a subsequent diagnosis of GD. This reverse sequence highlights the need to consider the potential presence of underlying endocrine disorders in cases of abnormal chest imaging findings, and it underscores the importance of a comprehensive diagnostic approach in similar scenarios.

The mechanisms by which GD induces thymic hyperplasia differ between TTH and FTH patients. The administration of T3 in mice or T4 in rats induces thymic enlargement (12,13), suggesting a direct role of thyroid hormones in thymic hypertrophy. Additionally, thyroidectomy in adult rats results in thymic cortical atrophy, which is reversed by T4 administration, further supporting the contribution of thyroid hormones to thymic maintenance (14). Thymic epithelial cells express nuclear T3 receptors and thyroid hormones stimulate thymocyte differentiation, thus providing a potential mechanistic link (15). These reports suggest that excessive thyroid hormone levels contribute to TTH development. However, the detailed mechanism by which thyroid hormones induce thymic enlargement remains unclear. In contrast, FTH is thought to be involved in autoimmune mechanisms. FTH is associated with autoimmune diseases, particularly with MG. Notably, in early onset myasthenia gravis (EOMG), FTH is observed in 50-60% of cases. An inflammatory response centered on interferon-beta triggers FTH in EOMG; however, the precise pathogenesis of FTH remains unknown (16). FTH has been hypothesized to serve as a major site for the production of autoantibodies, particularly EOMG, which underpins the efficacy of thymectomy as a therapeutic intervention (17). Regarding the relationship between GD and FTH, Murakami et al. identified TSH receptors in the thymic epithelial cells (18) and demonstrated that these receptors are functionally active (19). These findings suggested that TRAb directly influences thymic cells by activating TSH receptors, thereby inducing FTH. Therefore, FTH is believed to be associated with GD.

Several studies have suggested a relationship between the autoimmune mechanisms underlying GD and FTH. Notably, Song et al. (20) and Tsukada et al. (21) reported a significant correlation between TRAb titers and thymic enlargement, supporting the hypothesis that autoimmunity plays a role in FTH pathogenesis in GD. Furthermore, Fang et al. (22) demonstrated that in most patients undergoing radioactive iodine therapy, the TRAb levels exhibited a transient increase within the first year of treatment, followed by a subsequent decline approximately one year post-treatment. In the present case, no thymic enlargement was observed on a CT scan performed five months after radioiodine therapy. However, the thymus was not evaluated during the study period. Therefore, the chronological changes in the thymus following therapy remain unclear. Given these findings, it is plausible that radioiodine therapy may contribute to the induction of thymic enlargement, warranting further investigation of its underlying mechanisms and clinical implications. In contrast, Scappaticcio et al. reported that thymic hyperplasia associated with GD typically resolves within 12 months of initiating treatment. Interestingly, half of the patients with resolved thymic hyperplasia maintain persistently positive TRAb levels (10). In a related study, Jinguji et al. examined changes in thymic volume in 40 GD patients before and after radioiodine therapy. Their findings revealed a positive correlation between reduction in thymic volume and serum T3 levels but no significant association with changes in TRAb levels (23). A key limitation of this study is that the TRAb levels were measured only at baseline, precluding the ability to establish a causal relationship between TRAb levels and the regression of thymic hyperplasia.

One of the distinctive clinical features of this case was the administration of radioiodine therapy for the treatment of GD. The thymus expresses the sodium/iodide symporter (24,25); however, its iodine uptake capacity is substantially lower than that of the thyroid gland (26). Although the direct cytotoxic effects of ¹³¹I on thymic epithelial cells may contribute to thymic involution, only technetium scintigraphy was performed in the present case for GD diagnosis, which does not allow for the assessment of thymic iodine uptake. To properly evaluate this possibility, ¹²³I scintigraphy would be required, as it enables visualization of iodine uptake by the thymus. Consequently, it remains uncertain whether radioactive iodine therapy contributed to the regression of thymic hyperplasia in this patient.

Another notable clinical feature of this case was the elevated sIL-2R level, a marker commonly associated with malignant lymphoma, which normalized three months after the initiation of GD treatment. Tsukada et al. (21) and Ogawa et al. (27) reported a correlation between the regression of thymic hyperplasia and normalization of sIL-2R levels following treatment for GD. These findings suggest that sIL-2R may serve as a potential biomarker for monitoring the disease activity and progression of thymic hyperplasia associated with GD. This marker is elevated during thyrotoxicosis and normalizes following the restoration of thyroid function (28). Interleukin-2 (IL-2) and its receptor play critical roles in regulating immune system function primarily through their effects on T lymphocytes (29). Although the physiological role of sIL-2R remains incompletely understood, its elevation in thyrotoxicosis and potential involvement in thymic hyperplasia necessitate further investigation.

In patients with GD who present with thymic enlargement, it is crucial to consider the possibility of malignant disease. If a thorough evaluation reveals no findings suggestive of malignancy, thymic enlargement can be regarded as thymic hyperplasia associated with GD, and GD treatment must be prioritized. Although a histological diagnosis through biopsy and frequent imaging studies are optimal methods for monitoring thymic enlargement, the invasive nature of these tests poses a concern. To address this issue, IL-2R can be used as a marker for disease activity in thymic hyperplasia. If the IL-2R levels decrease in response to GD treatment, thymic hyperplasia should be considered, potentially reducing the need for frequent imaging studies. Conversely, if the IL-2R levels remain unchanged despite treatment, causes of thymic enlargement other than thymic hyperplasia must be considered. However, this clinical approach is associated with several limitations. Notably, there is insufficient evidence regarding the relationship between IL-2R and thymic hyperplasia and the mechanisms by which T3 induces thymic hyperplasia remain poorly understood. These gaps highlight the need for further investigation of the clinical and molecular mechanisms. Furthermore, determining whether thymic enlargement is attributable to thymic hyperplasia associated with GD, warranting a focus on medical management, or whether alternative underlying conditions necessitate surgical intervention, requires a comprehensive evaluation incorporating the findings from imaging studies, histopathological examinations, and other relevant diagnostic tools.

We herein described a case in which an investigation of an abnormal chest shadow led to the diagnosis of GD. The anterior mediastinal tumor, identified as the cause of the abnormal chest shadow, was ultimately determined to be thymic hyperplasia associated with GD based on the clinical course. This case underscores the importance of considering thymic hyperplasia as a potential GD complication.

Written informed consent was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).