A Unique Presentation of Metastatic Follicular Thyroid Cancer Associated with Hyperthyroidism and an Active Graves’ Orbitopathy

Abstract Background: Graves orbitopathy (GO) developing in a thyroidectomized patient with hormonally active metastatic follicular thyroid cancer (FTC) is an extremely rare event. We report a unique patient with GO and hyperthyroidism developing 13 years after FTC diagnosis. Case: A 79-year-old Caucasian female diagnosed with FTC T3N0M1 with lung metastases in 2005, was treated with total thyroidectomy and cumulative radioiodine (RAI) activity of 700 mCi between 2005 and 2010, with post-treatment scans revealing RAI-avid disease. Despite RAI treatment-associated stable disease in the lungs, the patient developed bone metastases and required external beam radiation (EBRT; 30 Gy in 10 fractions) to the left acetabular lesion in 2011. In 2015, she presented with clinically symptomatic tumor growth in the lungs and bones and biochemical disease progression with thyroglobulin levels rising from 255 ng/ml in 2014 to 273141 ng/mL in 2019. The patient completed repeat EBRT to the left iliac bone in December 2019 (30 Gy in 10 fractions). She was on weight-based suppressive levothyroxine treatment between 2005 and 2019 until she developed atrial fibrillation with a rapid ventricular response and was diagnosed with thyrotoxicosis with TSH < 0.01 mIU/mL (normal0.36 - 5.60) and free T4 5.93 ng/dL (normal 0.9 - 1.7). An iatrogenic cause of thyrotoxicosis was ruled out on the basis of persistent clinical and biochemical hyperthyroidism after reduction, and subsequently, cessation of levothyroxine treatment. Further workup was significant for elevated thyroid stimulated immunoglobulin (TSI) of 23.9 IU/l (normal: < 1.3) and thyrotropin receptor antibodies (TRAb) of 10.39 IU/L (< or =1.75), consistent with Graves’ disease. The patient achieved and maintained euthyroidism on methimazole treatment. In April 2019, she was diagnosed with active GO and was treated with intravenous methylprednisolone, which was discontinued four weeks later due to steroids-induced severe myopathy. Given a high clinical activity score of 6 and magnetic resonance imaging of the orbits revealing a significant bilateral symmetric extraocular muscle enlargement and increased retro-orbital fat with no evidence of optic nerve compromise, she underwent radiation therapy to the orbits (20 Gy in 10 fractions), which was completed in December 2019. Subsequently, in 2020, the patient underwent 8 cycles of treatment with a monoclonal antibody against insulin-like growth factor I receptor - teprotumumab. Subjectively, she reported improved eye swelling and no vision changes, but developed drug-induced partial hearing loss, which is thought to be reversible. Conclusion: Metastatic, progressive FTC can be associated with an autoimmune response, leading to stimulation of well-differentiated cancer tissue to overproduce thyroid hormones resulting in overt hyperthyroidism, as well as retroorbital fibroblasts activation leading to GO.