Radiotherapy-associated euthyroid Graves ophthalmopathy following floor-of-mouth surgery: a case report.

Abstract

The thyroid gland is commonly included in the radiation field during treatment of nonthyroidal neoplastic disease of the head and neck. As a result, thyroid abnormalities sometimes occur following external irradiation. We report an unusual case of radiotherapy-associated Graves ophthalmopathy 5 months after adjuvant external irradiation of the head and neck in a euthyroid patient who had undergone wide local excision of squamous cell carcinoma from the floor of the mouth.

Introduction

The thyroid gland is often included in the radiation field when patients with Hodgkin disease, non-Hodgkin lymphoma, and head and neck tumors are treated with external radiation therapy. As a consequence, thyroid abnormalities, especially hypothyroidism, are common in these patients. (1) Primary hypothyroidism is the most common thyroid sequela following radiotherapy. Most reports cite a hypothyroidism incidence of 20 to 30% in nonthyroidectomized head and neck cancer patients, (2-4) compared with an incidence in the general population of 8 to 10% in women and 1 to 2% in men. (5) In contrast, Graves disease following external irradiation is not well recognized and is extremely rare, having a reported incidence of 2% when manifested as hyperthyroidism and 0.2% when manifested as ophthalmopathy. (6)

The thyroid disease described by Robert Graves (7) and now known as Graves disease is part of a syndrome that consists of hyperthyroidism, goiter, ophthalmopathy and, occasionally, dermopathy referred to as pretibial or localized myxedema. The terms Graves disease and hyperthyroidism are not synonymous because some patients have ophthalmopathy with no evidence of clinical hyperthyroidism. Graves ophthalmopathy is an autoimmune disease in which the volume of both the extraocular muscles and retro-orbital connective tissues is increased. (8,9)

At diagnosis of Graves hyperthyroidism, approximately 20 to 25% of patients have clinically obvious Graves ophthalmopathy that includes proptosis and periorbital edema, excluding the eye signs of thyroid hormone excess (lid retraction and stare). (9) However, on ultrasonography, computed tomography (CT), or magnetic resonance imaging of the orbits, many more patients have evidence of ophthalmopathy, primarily enlargement of retro-ocular muscles. (10)

Similarly, most patients with ophthalmopathy have evidence of thyroid disease, but in about 10% of patients, thyroid disease is not clinicallyobvious. (8) Such patients are labeled as having "euthyroid" Graves ophthalmopathy, but they often have high serum antithyroid autoantibody concentrations or circulating thyroid-specific T cells. (11)

We report a case, to our knowledge the first such report, of radiotherapy-associated euthyroid Graves ophthalmopathy following excision of squamous cell carcinoma from the floor of the mouth.

Case report

A 49-year-old euthyroid man with no family history of thyroid disease was referred to our clinic with biopsy-identified squamous cell carcinoma of the floor of the mouth. A spiral CT of the neck, from the skull base through the lung apices, was performed. A region of increased density measuring 1.5 x 1.5 cm, consistent with a mass, was identified in the anterior floor of the mouth. The lesion was below the intrinsic tongue musculature but within the mucosa overlying the extrinsic tongue musculature, abutting and possibly involving the anterior portions of the genioglossus and mylohyoid muscles (figure 1).

[FIGURE 1 OMITTED]

Wide local excision of the floor of the mouth was performed, and the neoplasm was noted to be approximately 2.0 x 1.5 cm. The specimen was sent for frozen section, and margins proved to be negative. However, on final pathologic evaluation, the deep margin was positive. After an uneventful recovery, the patient was seen in radiation oncology for postoperative adjuvant radiotherapy.

Per protocol, the patient received radiation to the primary site and the regional nodes with a combination of photons and electrons. The primary site and upper cervical nodes received 5,960 cGy, and the lower cervical and supraclavicular nodes received 5,040 cGy. A midline block partially shielded the larynx and the thyroid gland (figure 2). The estimated dose to the thyroid gland was less than 5,000 cGy, with about 50% of the gland receiving less than 3,000 cGy.

Approximately 5 months after postoperative radiotherapy, the patient experienced diplopia and was referred to an ophthalmologist, who suspected Graves ophthalmopathy. CT of the orbit revealed diffuse enlargement of the belly of the extraocular muscles, consistent with class IV ophthalmopathy according to the guidelines of the American Thyroid Association (12) (figure 3). Subsequently, the patient was referred to an endocrinologist, who noted on physical examination a diffusively enlarged symmetrical thyroid gland with left eye proptosis. The patient had no classic symptoms of hyperthyroidism (heat intolerance, palpitations, weight loss) and had gained 6 pounds since his radiation treatment.

[FIGURE 2 OMITTED]

Diagnostic thyroid function testing was conducted and revealed a thyrotropin level of less than 0.018 mIU/L (normal, 0.40 to 4.00 mIU/L), a [T.sub.3] level of 229.0 ng/dl (normal, 82 to 179 ng/dl), and a free [T.sub.4] level of 2.010 ng/dl (normal, 0.8 to 1.9 ng/dl). The patient's serum thyrotropin immunoglobulin level was slightly elevated at 220 mg/dl (normal, <130 mg/dl), confirming Graves disease. Although the patient's free [T.sub.4] level was slightly elevated and his thyrotropin level was abnormally low, he appeared clinically euthyroid and was not treated with antithyroid medications. He received prednisone for his Graves ophthalmopathy, and with the use of prisms his vision improved. Subsequent serial testing (at 1-month intervals) of serum thyroid function and thyrotropin autoantibodies showed a spontaneous return to normal levels. Prednisone therapy was discontinued, and after 2 years, the patient continues to be euthyroid with stable Graves ophthalmopathy and no recurrence of carcinoma.

[FIGURE 3 OMITTED]

Discussion

Radiation therapy is widely used to treat lymphomas and tumors of the central nervous system and head and neck. Exposure of nontarget organs, such as the thyroid gland, potentially leading to adverse effects, is unavoidable. Radiation effects on the thyroid gland were first reported in the 1920s. (13) In 1973, Wasnich et al reported euthyroid Graves ophthalmopathy after neck irradiation for nonthyroidal tumors in 2 patients: 1 being treated for Hodgkin lymphoma and 1 receiving adjuvant radiotherapy after radical mastectomy for carcinoma. (12) A 1991 retrospective analysis of 1,787 patients with Hodgkin disease who had been treated with external irradiation revealed that Graves hyperthyroidism developed in 30 patients, with concomitant ophthalmopathy in 17, but Graves ophthalmopathy with maintenance of a euthyroid state occurred in only 1 patient. (6) Graves ophthalmopathy with concomitant hyperthyroidism is more commonly reported following radiation treatment. (14-16)

Radiotherapy-induced ophthalmopathy associated with Graves disease most likely results from an autoimmune reaction secondary to a thyroid injury caused by the radiation. Evidence for this premise is the development or worsening of Graves ophthalmopathy after radioiodine therapy for Graves hyperthyroidism. (17-22) The changes are often mild and transient, at least in patients who have mild or no ophthalmopathy before treatment. Wasnich et al postulated that the ophthalmopathy observed after external irradiation in their patients and that seen after radioiodine therapy resulted from similar pathogenic processes. (12)

Further, the histologic effects of external radiation and gamma (radioiodine) on the thyroid have been shown to be qualitatively similar. (21) High doses of irradiation initially produce acute epithelial injury, associated with necrotizing vasculitis and thrombosis. Some investigators postulate that the coincident release of thyroid cell components, namelythyrotropin-receptor antigen, is the antigenic stimulus for the post-treatment rises in serum antithyroid antibodies that have been observed. (12)

Mechanistic observations, plus the frequent concomitant occurrence of Graves hyperthyroidism and Graves ophthalmopathy, have led to the suggestion that activation of the immune system must be secondary to an antigen shared by both tissues. The presence of the thyrotropin receptor messenger ribonucleic acid (mRNA) and protein in orbital fibroblasts and adipocytes suggests that mRNA may be the antigen involved in the pathogenesis of ophthalmopathy. (8,22-24)

In radioiodine treatment for hyperthyroidism, post-treatment rises of serum antithyroid antibodies can be dramatic and usually occur within 2 to 6 months. (25) These observations are strikingly similar to our reported case, in which serum antibody levels increased within this time period (but were mild and transient). The obvious difference is that our patient had a normal thyroid gland before irradiation and no evidence of orbitopathy.

Radiotherapy-associated thyroid abnormalities are underestimated and underreported, and as use of radiation therapy in head and neck tumors continues to expand, thyroid abnormalities due to inadvertent thyroid injury are likely to increase. Our case report supports Wasnich's hypothesis that a thyrotropin-receptor antigenic stimulus following external irradiation injury leads to Graves ophthalmopathy. A similar phenomenon in radioiodine-induced exacerbation of Graves ophthalmopathy in the treatment of hyperthyroidism has been well documented.

The total radiotherapy dose and radiation volume to the thyroid gland are among the most important risk factors for development of Graves disease and other thyroid abnormalities. Therefore, minimal exposure of the thyroid gland during neck irradiation and careful, long-term evaluation of thyroid function after radiotherapy are essential in managing this rare and unusual complication.

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James J. Jaber, MD, PhD; Frank J. Thomas, MD; Mathew J. Carfrae, MD; Lisa T. Galati, MD

From the Department of Otolaryngology--Head and Neck Surgery (Dr. Jaber, Dr. Carfrae, Dr. Galati) and the Department of Radiation Oncology (Dr. Thomas), Albany Medical College, Albany, New York. Dr. Jaber is now with the Department of Otolaryngology--Head and Neck Surgery, Loyola University Medical Center, Maywood, Illinois.

Corresponding author: James J. Jaber, MD, PhD, Loyola University Medical Center, 2130 S. First Ave., Maywood, IL 60153. Phone: [phone]; e-mail: [e-mail]