Graves' Ophthalmopathy on ⁶⁸Ga-DOTANOC Positron Emission Tomography/Computed Tomography

Figure 1a–i shows ⁶⁸Ga-DOTANOC positron emission tomography/computed tomography (PET/CT) orbital cross-section in three different patients (control, patient 1, and patient 2) with physiologic pituitary uptake seen in all three patients (yellow arrows). Figure 1a–c shows sections in a 44-year-old male with a history of pheochromocytoma (taken as control for Graves' ophthalmopathy [GO] group). Scan shows normal extraocular muscles (EOM) with no abnormal uptake (c, white arrow). Figure 1d–f shows sections, in a 65-year-old woman with severe GO (left > right), initially managed for her thyroid eye disease with pulse intravenous methyl prednisolone (6 gm) and left orbital decompression but showed delayed response to treatment. Scan shows bulky EOM (left > right) (e and f, white arrow) with somatostatin receptor (SSTR) expression. Neck sections showed enlarged both lobes of thyroid with increased tracer uptake, with a large nodule in the left lobe (d, black arrow) and also retrosternal extension from the right lobe forming a globular mass (d, red arrow). Fine-needle aspiration cytology from the left lobe cold nodule showed benign adenomatous changes (Bethesda 2). Her thyroid profile suggested hyperthyroid status, fT4 – 2.68 ng/dl (0.9–1.7 ng/dl), fT3 – 5.6 pg/ml (2–4.4 pg/ml), and thyroid stimulating hormone (TSH) <0.005 μIU/ml. For thyroid dysfunction, she was started on antithyroid drug (tablet carbimazole 30 mg/day) which was increased to 40 mg/day. Total thyroidectomy is planned after achieving the euthyroid status. Figure 1g–i shows sections in a 38-year-old woman with severe GO initially treated with oral glucocorticoids. Orbital sections show bulky superior rectus muscle (h and i, white arrow) with SSTR expression. Neck sections showed enlarged both lobes of thyroid showing increased tracer uptake with the presence of pyramidal lobe. Her thyroid profile suggested subclinical hyperthyroid profile, total T4–5.64 μg/dl (5.1–14.1 μg/dl), total T3–151 ng/dl (80–200 ng/dl), and TSH 0.028 μIU/ml. For thyroid dysfunction, she was started on antithyroid drug (tablet carbimazole 20 mg/day).

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Figure 1 ⁶⁸Ga-DOTANOC positron emission tomography/computed tomography (control, patient 1, and patient 2). (a-c) Control (pheochromocytoma) showing normal extraocular muscles with no abnormal uptake (c, white arrow). (d-f) A 65-year-old woman with severe Graves' ophthalmopathy showing bulky extraocular muscles with somatostatin receptor expression. Neck shows enlarged thyroid with increased tracer uptake and retrosternal extension forming a globular mass (red arrow). (g-i) A 38-year-old woman with severe Graves' ophthalmopathy showing bulky extraocular muscles (white arrow) with somatostatin receptor expression. Neck sections showing enlarged both lobes of thyroid with pyramidal lobe

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GO is an extrathyroidal manifestation of Graves' disease.[12] It involves autoimmune activation of fibroblasts, through different autoantigens, commonly involving thyrotropin receptor.[3] Lymphocytes also play a crucial role. Cluster differentiation (CD4+) T-lymphocytes cause activation of fibroblasts by forming CD40–CD154 bridges.[4] Other mononuclear cells including CD8+ T-cells, B-cells, and plasma cell are also involved, resulting in chronic inflammation in orbital tissue.[5] All these factors cause hyperplasia of adipose tissue, accumulation of glycosaminoglycans resulting in expansion of EOMs, and periorbital soft tissue.[6] In a study by García-Rojas et al., they demonstrated, sensitivity of 18F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT in detecting inflammation in GO is superior to other anatomical imaging methods.[7] However, one limitation of ¹⁸F-FDG PET/CT is the presence of physiological muscle uptake which can create difficulties in interpretation.[8] The molecular basis of using SSTR imaging in assessing GO is the expression of SSTRs in the cells associated with chronic inflammation in active GO.[9] Few previous studies have demonstrated SSTR expression in periorbital tissue using ¹¹¹In-pentetreotide scan (Octreoscan) and have also shown that intensity of uptake correlates with clinical stage of GO.[1011] SSTR expression in active GO has also been demonstrated using ⁶⁸Ga-DOTANOC PET/CT.[12] This also forms the basis for using long-acting somatostatin analogs as a treatment option for refractory GO patients because these peptides inhibit lymphocyte activation, proliferation, and cytokine production.[13] ⁶⁸Ga-DOTANOC PET/CT shows no physiological orbital muscle uptake as shown in the control patient Figure 1a–c. It can also possibly provide information that can be used in response assessment of patients treated with standard therapies and screening patients who fail to respond to conventional treatment, for newer therapies such as long-acting somatostatin analogs.