Bilateral orbital involvement of IgG4-related disease detected on 18F-Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography

Abstract Rationale: IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibro-inflammatory condition, which could involve multiple structures, including the pancreas, salivary glands, and lymph nodes. However, cases of IgG4-RD involving the bilateral orbits, salivary glands, submandibular glands, lymph nodes, and prostate are rare. Patient concerns: A 51-year-old man complaining of bilateral exophthalmos, reduced vision, and weight loss of 15 kg over 2 years presented to our department for evaluation. Diagnoses: Based on the elevated serum IgG4 level, postoperative pathology, and the features of 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), which revealed diffuse increased FDG uptake in many structures, he was diagnosed with IgG4-related disease involving the bilateral orbits, salivary glands, submandibular glands, lymph nodes, and prostate. Interventions: Because of the significant bilateral proptosis and exposure keratoconjunctivitis in the right eye, bilateral soft-tissue masses located in the orbits were resected, and the patient was started on oral methylprednisolone with gradual tapering. Outcomes: The patient's symptoms gradually relieved after the operation and glucocorticoid therapy. Four months later, cranial axial CT revealed remarkable narrowing of soft-tissue masses in the bilateral orbits, and his serum IgG4 level reduced sharply. Lessons: IgG4-RD should be considered in cases of diffuse FDG uptake in the bilateral orbits, salivary glands, submandibular glands, lymph nodes, and prostate on PET/CT.


Case presentation
A 51-year-old man presented with bilateral exophthalmos, reduced vision, and weight loss of 15 kg over 2 years. He had a history of type 2 diabetes, which was well-controlled with metformin. Physical examination revealed decreased visual acuity of 0.5 in the right eye and 0.2 in the left eye, elevated intraocular pressure of 22 mmHg in the right eye and 23 mmHg in the left eye, bilateral exophthalmos, ocular motility disturbance, and exposure keratoconjunctivitis in the right eye. Contrast-enhanced cranial axial CT ( Fig. 1 A and B) and magnetic resonance imaging (MRI) (Fig. 1 D-F) demonstrated significant homogeneously enhancing soft-tissue masses (white arrows) in the bilateral orbits and crowding of the optic nerves, especially on the right side. He was tentatively diagnosed with orbital tumor based on the CT and MRI findings. The serum tumor marker test showed slightly elevated carbohydrate antigen 72-4 and neuron-specific enolase levels at 7.18 U/mL (reference range, < 6.5 U/mL) and 16.21 ng/mL (reference range, < 15 ng/mL), respectively, but normal levels of all other tumor markers, including alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 15-3, carbohydrate antigen 19-9, cancer antigen 125, and total prostatespecific antigen.
Because of the severe bilateral proptosis and exposure keratoconjunctivitis in the right eye, soft-tissue masses located in the bilateral orbits were resected. The postoperative pathology showed fibrous hyperplasia with infiltrations of many lymphocytes and plasma cells. Immunohistochemical staining revealed that the lymphocytes and plasma cells were positive for IgG4 (more than 50 cells/high-power field), IgG, CD20, CD3e, CD23, CD138, with a Ki-67 proliferation index of about 5% to 10%, but negative for CD10 and CyclinD1. No IgH/Igk gene rearrangement peaks were detected. Combined with the aforementioned morphological findings and immunohistochemical staining and gene rearrangement results, the diagnosis of IgG4-RD was confirmed.
The patient was started on 40 mg of oral methylprednisolone daily, which was gradually tapered. His symptoms gradually relieved after the surgery and glucocorticoid therapy. Four months later, cranial axial CT (Fig. 1C) revealed remarkable narrowing of the bilateral soft-tissue masses (red arrows) and slight enlargement of the left lacrimal gland (red crossed arrow). Further, his serum IgG4 level reduced to 0.647 g/L (reference range, 0.035-1.5 g/L).
The patient provided informed consent for publication of this case.
The diagnosis of IgG4-RD is based on the characteristic histopathologic findings on biopsy and immunohistochemical staining results, including lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, accompanied by fibrosis, with storiform features, and often accompanied by obliterative phlebitis and modest tissue eosinophilia. [10,30] Although elevated serum IgG4 levels are not diagnostic, the serum IgG4 level should be measured because isolated elevated levels are a significant diagnostic aid. [31,32] Although the diagnosis of IgG4-RD requires the presence of characteristic findings in the biopsy specimen of the affected tissues, additional organ involvement can be identified through a careful history, physical examination, routine laboratory testing, and selected imaging. [30] Generally, CT of the chest, abdomen, and pelvis are performed for patients diagnosed with IgG4-RD because of the high frequency of subclinical disease. [30] If available, 18 F-FDG PET/CT can also be highly effective in determining the disease extent and should be considered at baseline. [9,30,33] A prospective cohort study evaluating the value of 18 F-FDG PET/CT in characterizing IgG4-RD revealed that 18 F-FDG PET/CT can reveal more organ involvement compared to conventional evaluations, including physical examination, ultrasonography, and CT. [9] Moreover, comprehensive understanding of all involvement can aid the biopsy-site selection. [9] In addition, 18 F-FDG PET/CT can monitor the therapeutic response after 2-4 weeks of steroid-based therapy. [9] The specific characteristics and pattern of IgG4-RD on 18 F-FDG PET/CT include diffusely elevated FDG uptake in multiple structures, including the pancreas, salivary glands, and retroperitoneal region. [9,30] Most patients with IgG4-RD respond to glucocorticoids within several weeks, typically with symptomatic improvement, reduction in the size of masses or organ enlargement, improvement in organ www.md-journal.com function, and often, reduction in serum IgG4 levels. [33,34] The natural history of IgG4-RD has not been well-defined. Some cases improve temporarily without treatment, but most cases progress at variable rates. [11,34] In 2010, Vege et al reported that 47% of the patients with type 1 AIP (the first disease recognized to be associated with IgG4-RD) experienced a relapse and that diffuse pancreatic swelling and proximal biliary involvement can predict recurrence. [24] In conclusion, we presented rare 18 F-FDG PET/CT images with intense diffuse FDG uptake in the bilateral orbits, salivary glands, submandibular glands, lymph nodes, and prostate. This report suggests that IgG4-RD should be considered in cases of diffuse FDG uptake in the bilateral orbits, salivary glands, submandibular glands, lymph nodes, and prostate on PET/CT. In addition, 18 F-FDG PET/CT is a useful diagnostic modality for patients with IgG4-RD, which can evaluate organ involvement, aid in biopsysite selection, and monitor the therapeutic response.