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Thymic Hyperplasia Presenting as Anterior Mediastinal Mass in 2 Patients With Graves Disease

      Graves disease is an autoimmune thyroid condition characterized by the production of autoantibodies against the thyrotropin receptor. The autoantibodies mimic the effect of the hormone on thyroid cells, which stimulates autonomous production of thyroxine and triiodothyronine. It has been hypothesized that cross-reactivity of autoantibodies may result in Graves ophthalmopathy and dermopathy. A seldom-recognized feature of Graves disease is thymic hyperplasia. We report 2 patients with Graves disease and incidentally discovered anterior mediastinal masses presumed to be thymic hyperplasia. In both cases, these masses regressed spontaneously after treatment of hyperthyroidism.
      Thymic involvement occurs to varying degrees in several autoimmune diseases.
      • Levinson AI
      • Zweiman B
      • Lisak RP
      Immunopathogenesis and treatment of myasthenia gravis.
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      The most notable of these is myasthenia gravis,
      • Vincent A
      • Palace J
      • Hilton-Jones D
      Myasthenia gravis.
      in which the thymus plays a pivotal role in the pathogenesis of the disease,
      • Levinson AI
      • Zweiman B
      • Lisak RP
      Immunopathogenesis and treatment of myasthenia gravis.
      and thymectomy frequently results in clinical improvement.
      • Olanow CW
      • Wechsler AS
      • Sirotkin-Roses M
      • Stajich J
      • Roses AD
      Thymectomy as primary therapy in myasthenia gravis.
      Thymic hyperplasia in Graves disease is more likely to be associated with, rather than the cause of, hyperthyroidism because hyperthyroidism persists after thymectomy.
      • Van Herle AJ
      • Chopra IJ
      Thymic hyperplasia in Graves' disease.
      Conversely, treatment of hyperthyroidism with antithyroid drugs results in a decrease in the size of the thymus.
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      Thus, in contrast to myasthenia gravis, an anterior mediastinal mass associated with hyperthyroidism may not need to be resected.

      REPORT OF CASES

      Case 1

      A 29-year-old previously healthy man presented with a 4-month history of weight loss accompanied by increased appetite, tachycardia, palpitations, increased sweating, and mild nervousness. In addition, he developed red and irritated eyes but denied any periorbital swelling or diplopia. He reported a sensation of fullness in his neck accompanied by some shortness of breath. There was no substantial change in bowel habits and no heat intolerance. Medical history, social history, and family history were noncontributory, and the patient took no medications.
      Physical examination was notable for an emaciated, anxious-appearing man with a fine tremor and tachycardia at a rate of 120 beats/min. His skin was moist and clammy. Inspection of the conjunctivae and lids showed red and irritated eyes with some lid retraction but no periorbital edema. Hertel exophthalmometer readings were normal at 17 mm bilaterally over a base of 112 mm. The thyroid gland was nontender but enlarged to at least 5 times its normal size with pronounced bruits audible over both sides. There were no nodules nor any evidence of neck lymphadenopathy. Findings on the remainder of the examination were unremarkable.
      Graves disease was suspected, and it was supported by laboratory evaluation showing a substantially depressed sensitive thyrotropin level of less than 0.004 mlU/L (reference ranges shown parenthetically) (0.30-5.0 mlU/L), a highly elevated total thyroxine level of 42.8 g/dL (5.0-12.5 g/dL), a free thyroxine level of more than 12 ng/dL (0.8-1.8 ng/dL), and a triiodothyronine level of 2002 ng/dL (80-180 ng/dL). A human immunodeficiency virus test was negative.
      A tuberculin skin test was positive, and isoniazid therapy was initiated subsequently. Chest radiography showed no parenchymal disease but revealed a large anterior mediastinal mass (Figure 1). Radioactive iodine uptake and scan showed diffuse, uniformly increased tracer accumulation throughout both lobes of the thyroid gland and throughout the isthmus, consistent with Graves disease, with 100% radioactive iodine uptake at 24 hours. The patient was given -blocker therapy for symptomatic relief, and he underwent treatment with 12 mCi of radioactive iodine I 131 with concurrent prednisone, 15 mg twice daily prophylactically, to prevent inflammation associated with radiation-induced thyroiditis.
      Figure thumbnail gr1
      Figure 1Posteroanterior chest radiograph showing the anterior mediastinal mass in case 1.
      Contrast computed tomography (CT), which was delayed for 2 days to facilitate immediate 131I therapy, revealed a homogeneous mass (7 × 3 cm) in the anterior mediastinum (Figure 2, left). The mass was suggestive of thymic hyperplasia. A biopsy was not performed. One week after 131I ablative therapy, the size of the patient's thyroid had decreased substantially, and prednisone was discontinued. At his 6-week follow-up, the patient had regained 6.8 kg and was clinically euthyroid. His total thyroxine level was low at 1.6 |g/dL, prompting initiation of L-thyroxine replacement. Repeated CT showed a decrease in the size of his anterior mediastinal mass, which continued to diminish over the ensuing weeks (Figure 2, right).
      Figure thumbnail gr2
      Figure 2Contrast computed tomography, axial cut, showing a large anterior mediastinal mass suggestive of thymic hyperplasia in case 1. Size of the mass at presentation (left) was 7 × 3 cm, and its size was markedly reduced 3 months later (right) after treatment with radioactive iodine I 131.

      Case 2

      A 41-year-old woman initially presented with numerous complaints, including weight loss, cough with shortness of breath, daily nausea, and disturbed bowel pattern. Findings on chest radiography at that time were normal. Hyperthy- roidism was considered, but her sensitive thyrotropin level was normal at 1.31 mlU/L. During the next 6 months, her weight decreased from 104 kg to 82 kg, and she developed obvious goiter, onycholysis, and weakness in her thighs.
      The patient's medical history was notable for obesity but was otherwise noncontributory. She took no medications and did not smoke or consume alcohol. Her family history was noncontributory.
      Physical examination revealed an obese woman with mild tachycardia and a fine tremor. Hertel exophthal- mometer readings were normal at 20 mm bilaterally over a base of 116 mm. The thyroid was enlarged bilaterally, approximately 2 to 2.5 times reference size, without discrete nodules. Onycholysis was apparent on multiple fingernails. Examination findings were otherwise unremarkable.
      Laboratory evaluation demonstrated an undetectable sensitive thyrotropin level of less than 0.004 mlU/L, and a positive thyroid stimulating immunoglobulin of 3.8 mlU/L (0-1.3 mlU/L), consistent with Graves disease. Noncontrast CT of the chest was performed to follow up on an “abnormality” reported on chest radiography done at an institution elsewhere to evaluate the patient's cough, dyspnea, and intermittent hemoptysis. The CT (Figure 3, left) showed diffusely increased soft tissue in the anterior mediastinum around the level of the aortic arch, separate from the patient's known goiter. Thymic hyperplasia was suspected.
      Figure thumbnail gr3
      Figure 3Noncontrast computed tomography, axial cut, showing an anterior mediastinal mass suggestive of thymic hyperplasia in case 2. Mass at presentation (left) and markedly reduced 6 months after the initiation of propylthiouracil (right).
      The patient was treated with propylthiouracil, 100 mg 3 times daily, and atenolol, 50 mg/d, and became clinically euthyroid. As her thyroid status stabilized, the anterior mediastinal mass continued to diminish, as seen on repeated CT (Figure 3, right) done 6 months after the initiation of propylthiouracil. The decreased thymic size in response to propylthiouracil supported the suspected diagnosis of thymic hyperplasia; thus, a biopsy was not performed.

      DISCUSSION

      Graves disease (autoimmune hyperthyroidism) is characterized by the production of antibodies for the thyrotropin receptor that stimulate thyroid functions and cause thyroid enlargement.
      • McIver B
      • Morris JC
      The pathogenesis of Graves' disease.
      Graves disease is most commonly seen in adults aged 20 to 50 years, and it is approximately 10 times more common in women, with an estimated incidence ranging from 15 to 50 per 100,000 persons per year.
      • Berglund J
      • Christensen SB
      • Hallengren B
      Total and age-specific incidence of Graves' thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo 1970-74.
      • Cox SP
      • Phillips DI
      • Osmond C
      Does infection initiate Graves disease? a population based 10 year study.
      • dos Remedios LV
      • Weber PM
      • Feldman R
      • Schurr DA
      • Tsoi TG
      Detecting unsuspected thyroid dysfunction by the free thyroxine index.
      • Furszyfer J
      • Kurland LT
      • McConahey WM
      • Elveback LR
      Graves' disease in Olmsted County, Minnesota, 1935 through 1967.
      • Galofre JC
      • Garcia-Mayor RV
      • Fluiters E
      • et al.
      Incidence of different forms of thyroid dysfunction and its degrees in an iodine sufficient area.
      The autoantibodies produced against the thyrotropin receptor in Graves disease mimic the effects of the hormone on thyroid cells, which stimulate autonomous production of thyroxine and triiodothyronine. However, patients commonly exhibit antibodies to several thyroidal antigens, including thyroperoxidase, thyroglobulin, and the thyroidal iodide transporter. Although the anti- thyrotropin receptor antibodies are clearly important in the pathogenesis of the disease, antithyroperoxidase and antithyroglobulin seem to have little role, serving instead as markers of thyroid autoimmunity and/or susceptibility.
      • McIver B
      • Morris JC
      The pathogenesis of Graves' disease.
      A clear association has been demonstrated between Graves disease and other autoimmune conditions, such as myasthenia gravis, Addison disease, type 1 diabetes mellitus, premature ovarian failure, and vitiligo.
      • Zelissen PM
      • Bast EJ
      • Croughs RJ
      Associated autoimmunity in Addison's disease.
      There is also an association between Graves disease and thymic hyperplasia.
      • Gunn A
      • Michie W
      • Irvine WJ
      The thymus in thyroid disease.
      Thymic involvement likely occurs to varying degrees in several autoimmune diseases, with myasthenia gravis being the best example.
      • Levinson AI
      • Zweiman B
      • Lisak RP
      Immunopathogenesis and treatment of myasthenia gravis.
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      The association between Graves disease and thymic hyperplasia was first recognized in 1929 by Hammar.
      • Hammar JA
      Kasuistischer Beitrag Zur frage nachdem Einfluss endokriner Erkrankungen, auf die Thymusdruse.
      Pathologically, approximately one third of patients with thyrotoxicosis will have microscopic abnormalities in the thymus consisting of medullary lymphoid follicles.
      • Michie W
      • Gunn A
      The thyroid, the thymus and autoimmunity.
      However, massive enlargement of the thymus detectable radiologically, as in our 2 cases, is uncommon and has been infrequently reported.
      • Van Herle AJ
      • Chopra IJ
      Thymic hyperplasia in Graves' disease.
      • Beddingfield GW
      • Campbell Jr, DC
      • Hood Jr, RH
      • Dooley BN
      Simultaneous disorders of thyroid and thymus: report of two cases.
      • Bergman TA
      • Mariash CN
      • Oppenheimer JH
      Anterior mediastinal mass in a patient with Graves' disease.
      • Ford HC
      • Savage T
      • Delahunt JW
      Anterior mediastinal mass and Graves' disease.
      • Franken Jr, EA
      Radiologic evidence of thymic enlargement in Graves's disease.
      • Hsu LH
      • Chen JC
      • Tsai GJ
      • Tsou MH
      • Hsu WH
      Thymic hyperplasia in a patient with Graves' disease.
      • Inoue K
      • Sugio K
      • Inoue T
      • Ishida T
      • Sugimachi K
      Hyperplasia of the thymic gland in a patient with Graves' disease.
      • Sandler M
      • Sacks G
      • Linde R
      • Shaff M
      The CT detection of thymic hyperplasia in association with thyrotoxicosis: case report.
      Information is limited concerning the pathophysiologic role of the thymus in Graves disease. In a review of the literature, 2 theories emerge. The first theory hypothesizes that the enlarged thymus may play an etiologic role in Graves disease, just as it does in myasthenia gravis. In contrast, the second theory argues that thymic hyperplasia is the result of Graves disease, and that treatment of Graves disease results in resolution of the thymic abnormality.

      Etiologic Role for the Thymus in Graves Disease?

      Older literature
      • Hammar JA
      Kasuistischer Beitrag Zur frage nachdem Einfluss endokriner Erkrankungen, auf die Thymusdruse.
      • Halsted W
      The significance of the thymus gland in Graves' disease.
      suggested that the hyperplastic thymus played an etiologic role in Graves disease as it does in myasthenia gravis. The thymus plays a central role in determining self- vs nonself-recognition by T cells, suggesting that an abnormality of thymic function could potentially be involved in the etiology of autoimmune thyroid disease.
      • McIver B
      • Morris JC
      The pathogenesis of Graves' disease.
      However, other than in rare cases of polyglandular autoimmune syndrome,
      • Leor J
      • Levartowsky D
      • Sharon C
      Polyglandular autoimmune syndrome, type 2.
      patients with Graves disease do not have obvious immune dysfunction aside from their predisposition to autoimmunity. Furthermore, in contrast to myasthenia gravis, removal of the enlarged thymus in patients with Graves disease does not reverse hyperthy- roidism.
      • Van Herle AJ
      • Chopra IJ
      Thymic hyperplasia in Graves' disease.
      Finally, as in our first case, the rapid regression of thymic hyperplasia after 131I therapy argues against autoimmunity as the clear cause of thymic hyperplasia because autoimmunity is frequently known to worsen transiently after radioactive iodine therapy.
      • DeGroot LJ
      Radioiodine and the immune system.

      Etiologic Role for Graves Disease in Thymic Hyperplasia?

      In patients with Graves disease and thymic hyperplasia, the thymic hyperplasia is more likely to be the result of, rather than the cause of, their Graves disease. Not only does hyperthyroidism persist after thymectomy
      • Van Herle AJ
      • Chopra IJ
      Thymic hyperplasia in Graves' disease.
      but also animal studies have shown a restoration of the atrophic thymic cortex in adult chickens after administration of thyroid hormone
      • Warner NL
      The immunologic role of different lymphoid organs in the chickens.
      and induction of thymic hyperplasia in mice with hyperthyroidism.
      • Scheif JM
      • Cordier AC
      • Haumont S
      Epithelial cell proliferation in thymic hyperplasia induced by triiodothyronine.
      Thyroid hormones may modulate secretion of thymic factors. For instance, Fabris et al
      • Fabris N
      • Mocchegiani E
      • Mariotti S
      • Pacini F
      • Pinchera A
      Thyroid function modulates thymic endocrine activity.
      showed that levels of thymulin, a thymic nonapeptide essential for T-lymphocyte differentiation and function, are elevated in hyperthyroid patients and lower in hypothyroid patients compared with healthy controls. Furthermore, thymulin changes could be reversed by correction of thyroid status in both groups of patients. Although thymic hyperplasia was not the focus of that study, the investigators nonetheless illustrated that thyroid function appears to affect thymic endocrine activity.
      In accordance with the suggestion that the hyperthyroid state may induce thymic hyperplasia, it has been shown that treatment with antithyroid drugs can induce rapid, although often incomplete, thymic involution. Murakami et al
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      studied thymic size and density in 23 untreated patients with Graves disease with use of CT. In comparison with 38 age-matched controls, both thymic size (calculated as the area of the thymus at the level where it appeared most prominently on CT) and density were higher in patients with Graves disease. After treatment with antithyroid drugs (either methimazole or propylthiouracil), both thymic size (852±245 mm2 before and 402±280 mm2 after treatment; P<.001) and density (9.1±50.7 Hounsfield unit before and −35.5±36.3 Hounsfield unit after treatment; P<.01) were significantly reduced, with a concomitant decrease in thyrotropin receptor antibodies (38.1%±17.5% before and 5.2%±5.8% after treatment; P<.001).
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      The decrease in thymic size and density by treatment with antithyroid drugs could be produced, at least in part, by an indirect action—lowering circulating thyroid hormone levels. In animal models, exogenous thyroid hormone administration resulted in increases in both cortical and medullary components of the thymus,
      • Ban T
      • Kosugi S
      • Kohn LD
      Specific antibody to the thyrotropin receptor identifies multiple receptor forms in membranes of cells transfected with wild-type receptor complementary deoxyribonucleic acid: characterization of their relevance to receptor synthesis, processing, structure, and function.
      while thyroidectomy resulted in a reduction in thymic size.
      • Fabris N
      Immunodepression in thyroid-deprived animals.
      However, investigators have also suggested that antithyroid drugs not only cause a block of thyroid hormone synthesis but also have immunosuppressive effects, including lowering thyrotropin receptor antibody levels.
      • Weetman AP
      • McGregor AM
      • Hall R
      Evidence for an effect of antithyroid drugs on the natural history of Graves' disease.
      It is tempting to speculate that antithyroid medication may also induce thymic atrophy by mechanisms related to their immuno- suppressive effects.
      With the exception of 2 atypical case reports describing thymic enlargement in patients with toxic nodular goier,
      • Appetecchia M
      • Tonachella R
      • Fabi A
      Toxic nodular goiter and thymic hyperplasia in an adult: case report.
      • White SR
      • Hall JB
      • Little A
      An approach to mediastinal masses associated with hyperthyroidism.
      thymic hyperplasia has been described primarily in the setting of hyperthyroidism caused by Graves disease, suggesting that autoimmunity could play a role in thymic hyperplasia.
      There is evidence that thymic hyperplasia in Graves disease may simply be part of a generalized lymphoid hyperplasia that characterizes a systemic autoimmune process. Lymphocytic infiltrates within the thyroid gland of patients with Graves disease have been recognized for many years.
      • Livolsi VA
      The presence of lymphocytic infiltrates also has been reported in the extraocular muscles of patients with Graves ophthalmopathy
      • Heufelder AE
      Involvement of the orbital fibroblast and TSH receptor in the pathogenesis of Graves' ophthalmopathy.
      and in subcutaneous tissue of patients with dermopathy.
      • Kiljanski J
      • Nebes V
      • Wall JR
      Significance of tissue specific and tissue non specific autoimmune reactions of Graves' disease.
      Splenomegaly and generalized lymphadenopathy have also been described.
      • Alsanea O
      • Clark OH
      Treatment of Graves' disease: the advantages of surgery.
      Similarly, histologic examination of the thymus of patients with Graves disease shows a thymic medullary lymphoid follicle formation with active germinal centers.
      • Gunn A
      • Michie W
      • Irvine WJ
      The thymus in thyroid disease.
      • Michie W
      • Gunn A
      The thyroid, the thymus and autoimmunity.
      In fact, Michie and Gunn
      • Michie W
      • Gunn A
      The thyroid, the thymus and autoimmunity.
      showed that approximately 38% of patients with thyrotoxicosis have a histologic change of the thymus gland that at biopsy shows the formation of medullary lymphoid follicles.
      Thymic thyrotropin receptor may be involved in developing thymic hyperplasia in patients with Graves disease by serving as an autoantigen. In 1 study, immunoglobulins from a patient with Graves disease and thymic hyperplasia promoted thymocyte mitogenesis in vitro.
      • Wortsman J
      • McConnachie P
      • Baker Jr, JR
      • Burman KD
      Immunoglobulins that cause thymocyte proliferation from a patient with Graves' disease and an enlarged thymus.
      Subsequently, Murakami et al
      • Murakami M
      • Hosoi Y
      • Negishi T
      • et al.
      Thymic hyperplasia in patients with Graves' disease: identification of thyrotropin receptors in human thymus.
      clearly showed the presence of thyrotropin receptor in nonneoplastic thymic tissue by polymerase chain reaction amplification, Northern and Western blot analysis, and immunohistochemistry. Their report was the first demonstration by Northern blot analysis of the full-length form of thyrotropin receptor transcripts in human tissues other than the thyroid gland. Thyrotropin receptor in thymic epithelial cells may be involved in the initiation or perpetuation of autoimmune response and in the selection of the T-cell repertoire that may contribute to the development of autoreactive T cells in Graves disease.
      The precise pathophysiology of thymic hyperplasia in Graves disease has not yet been determined. The thymus does not appear to play an obvious etiologic role, and thymectomy does not appear to be therapeutic for Graves disease. In contrast, thymic hyperplasia appears to be caused by Graves thyrotoxicosis, although the relative contributions of autoimmunity vs hyperthyroidism alone remain unclear. However, it has been shown that treatment of Graves disease results in the involution or regression of thymic hyperplasia, eliminating the need for thymic biopsy.

      Approach to a Thymic Mass in Patients With Graves Disease

      The differential diagnosis of an anterior mediastinal mass generally includes lymphoma, germ cell tumor, mesenchymal tumors, thyroid or parathyroid masses, metastatic tumors, thymic hyperplasia, and thymoma.
      • Morgenthaler TI
      • Brown LR
      • Colby TV
      • Harper Jr, CM
      • Coles DT
      Thymoma.
      In many settings, the discovery of an anterior mediastinal mass would likely prompt surgical resection. In fact, the earliest case reports describing anterior mediastinal masses associated with hyperthyroidism used median sternotomy and surgical resection of the thymus to diagnose benign thymic hyperplasia.
      • Van Herle AJ
      • Chopra IJ
      Thymic hyperplasia in Graves' disease.
      • Beddingfield GW
      • Campbell Jr, DC
      • Hood Jr, RH
      • Dooley BN
      Simultaneous disorders of thyroid and thymus: report of two cases.
      An association between thymic hyperplasia and Graves disease seems well established, and an anterior mediastinal mass associated with hyperthyroidism may not require resection or immediate biopsy. If an anterior mediastinal mass in a thyrotoxic patient is detected on chest radiography, CT of the chest should be performed. If a homogeneous mass with no invasion to the neighboring tissue, no calcification, and no cystic lesion is observed, we suggest treating the patient's hyperthyroidism with close radiologic follow-up of the anterior mediastinal mass. A decrease in size of the mass after treatment of hyperthyroidism further supports the suspected diagnosis of thymic hyperplasia. Recognition of the association between thymic hyperplasia and Graves disease, and of the benign course after treatment of the hyperthyroidism, can spare patients from a major surgical procedure.

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