Immunoglobulin G4-related ophthalmic disease with orbital deep hemangioma: A case report

Abstract

Immunoglobulin G4-related ophthalmic disease is an autoimmune condition characterized histologically by dense lymphoplasmacytic infiltration, obliterative phlebitis, and storiform fibrosis. Orbital hemangioma is one of the most common primary orbital tumors in adults. The coexistence of immunoglobulin G4-related ophthalmic disease and orbital hemangioma is extremely rare. This report presents the case of a man in his early 30s diagnosed with immunoglobulin G4-related ophthalmic disease. He was treated with glucocorticoid therapy and gamma knife radiosurgery. Herein, we described the clinical presentation, imaging findings, histopathology, treatment, and outcomes of this rare case to provide a reference for future diagnosis and management.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disorder that often presents as mass-forming lesions, with elevated serum immunoglobulin G4 (IgG4) levels are observed in 55%–97% of all cases. ¹ When IgG4-RD affects the orbit and its adnexa, including the lacrimal glands, extraocular muscles, nerves, and orbital fat, it is termed as IgG4-related ophthalmic disease (IgG4-ROD).^2,3 Orbital hemangiomas are the most common benign primary orbital tumors in adults. ⁴ Common clinical manifestations of these conditions include proptosis, ptosis, restricted eye movement, and orbital swelling. Nontraumatic orbital hemorrhage (NTOH) may present with a sudden increase in exophthalmos accompanied with symptoms such as decreased vision or even vomiting. ⁵

Herein, we present a rare case of concurrent IgG4-ROD and a deep orbital hemangioma to contribute to a better understanding of the clinical features, diagnosis, and treatment of this uncommon presentation.

Case report

A case of orbital IgG4-ROD with orbital deep hemangioma recorded in the databases of the Ophthalmology and Pathology Departments of West China Hospital of Sichuan University from 2022 to 2025 was reviewed. This study was conducted as per the ethical considerations of the World Medical Association and the Declaration of Helsinki. Furthermore, the study was approved by the Ethics Committee of West China Hospital, Sichuan University (NO. 2025-584). The reporting of this study conforms to the Case Report (CARE) guidelines. ⁶ We obtained the patient’s consent before initiating treatment.

A man in his early 30s visited the Ophthalmology Department of West China Hospital of Sichuan University (Chengdu, China) in February 2022, presenting with a 1-year history of proptosis and redness in his left eye, which had worsened over the past week. He had no history of systemic diseases or allergies. Ophthalmic examination revealed a best-corrected visual acuity of 20/32 in the left eye, with an intraocular pressure of 34.8 mmHg measured via noncontact tonometry. Proptosis, conjunctival hyperemia, and edema of the left orbit, along with limited ocular motility in all directions, were observed (Figure 1(a)). Other ophthalmic examination findings were unremarkable. Imaging of the orbit showed a diffuse retrobulbar mass in the left orbit (Figure 1(b) to (f)). The patient underwent partial surgical resection, during which dark red blood was observed (Figure 1(g)). This procedure aimed to relieve the symptom of compression and obtain a sample for excisional biopsy. Pathological examination revealed a hemangioma with focal thrombosis (Figure 1(h) and (i)). The patient was advised to visit the clinic for a follow-up after 2 months; however, he did not adhere to the recommendation. One year later, he was readmitted with worsening swelling and proptosis of the left eye, which had persisted for 15 days (Figure 2(a)). Orbital contrast-enhanced magnetic resonance imaging (MRI) revealed a recurrent lesion, which was smaller than the previous one (Figure 2(b) to (e)). The MRI also showed an enlarged medial rectus muscle in the left eye with mixed intensity, and the maximum cross-sectional area of the tumor was approximately 2.92 cm × 1.43 cm. A second surgical procedure was performed, and the resected specimen appeared as gray-white, dark red masses (Figure 2(f)). Immunohistochemical (IHC) staining revealed 50–70 IgG4+ cells per high-power field (HPF) in the lesion (Figure 2(i) and (j)). The IHC staining also showed positive expression for CD20 and CD3 (Figure 2(k) and (l)) and negative expression for Epstein–Barr encoding region (EBER) (Figure 2(n)). Ki-67 staining indicated a low proliferative index of 5%–10%, which was primarily observed in the lymphatic follicles (Figure 2(m)). The serum IgG4 level was 3.0 g/L, with a reference range of 0.03–2.01 g/L. The patient was diagnosed with IgG4-ROD and a deep orbital hemangioma in the left orbit, which could be accompanied with nontraumatic orbital hemorrhage. The patient was then referred to the rheumatology and immunology department for further treatment, and whole-body imaging revealed no signs of systemic disease. A steroid-based therapeutic regimen with immunosuppressants was initiated for 6 months. During the following 5 months, the patient received high-dose pulse glucocorticoid therapy each month (a total of 4 g) and cyclophosphamide in the final month (a total of 5 g) at the hospital (Figure 3). Between the pulse therapy sessions, the patient was treated with low-dose oral steroids, which were gradually tapered (starting at 60 mg/day and reduced to 20 mg/day) (Figure 3). After the first pulse of steroids, folliculitis developed during the inter-pulse interval, prompting treatment discontinuation. Therefore, the steroid and immunosuppressant regimen was adjusted accordingly. During follow-up visits over the next 6 months, the patient’s ophthalmic clinical symptoms and mass growth were significantly controlled (Figure 4(a) to (d)). However, during the period when the patient was on low-dose glucocorticoids, the exophthalmos worsened, and orbital MRI showed an increase in the tumor size within the following 2 months (Figure 4(e) to (l)). This was accompanied with an adverse effect of drug-induced hypertension. Therefore, gamma knife radiosurgery (GKRS) was used as an additional treatment in the Neurosurgery Department of West China Hospital of Sichuan University. The left orbital mass was treated with 9 Gy to the 45% isodose line as a single fraction GKRS using a mask in December 2023. The left orbital mass was treated with 8 Gy to the 50% isodose line as a single fraction GKRS using a mask in March 2024. This led to a reduction in the lesion size over the next 3 months (Figure 4(m) to (p)). Fortunately, the patient’s vision remained unaffected over the long term, and at the time of writing this report, the patient is being followed up regularly.

Figure 1.

Ocular appearance, orbital imaging, and pathological images of the lesion specimen from the first surgery. (a) Preoperative image showing proptosis of the left eye with conjunctival congestion and edema. (b, c) Orbital CT revealing a large, homogeneous mass in the left orbit with inward displacement of the ethmoid bone. (d–f) MRI of the orbit demonstrating a large, irregular mass in the left orbit surrounding the optic nerve and medial rectus muscle. Additionally, a T2 high-signal area was observed in the left maxillofacial region and forehead with significant enhancement and nodular lesions. (g) The resected specimen appearing dark red, with a total size of approximately 7 cm × 6 cm × 1.2 cm and medium texture. (h–i) Pathological examination revealing the lesion to be a hemangioma with focal thrombosis and lymphoid follicles in the stroma. Hematoxylin and eosin staining: original magnifications, 100× (h) and 200× (i). CT: computed tomography; MRI: magnetic resonance imaging.

Figure 2.

Ocular appearance, orbital imaging, gross specimen, and pathological images of the lesion specimen from the second surgery. (a) Preoperative image showing proptosis of the left eye. (b–e) Orbital MRI revealing a moderate mass (4.1 cm × 2.5 cm) near the lateral orbital wall with homogeneous enhancement. (f) The resected tumor appeared gray-white and dark red, with a total size of approximately 3.7 cm × 3.2 cm × 1.7 cm, which was smaller than that of the specimen from the first surgery. (g–h) Pathological examination showing that the lesion was composed of hemangioma with focal thrombosis and lymphoid follicles in the stroma. Hematoxylin and eosin staining: original magnifications, 100× (g) and 200× (h). (i–j) Immunohistochemical staining revealing approximately 50–70 IgG4+ cells per HPF in the lesion (original magnification, 400×). (k) Lesion cells exhibiting partial cytoplasmic positivity for CD20 immunostaining (CD20: original magnification, 400×). (l) Lesion cells showing partial cytoplasmic positivity for CD3 immunostaining (CD3: original magnification, 400×). (m) Ki67 immunostaining demonstrating strong nuclear immunoreactivity in the lymphoid follicles of the lesion (original magnification, 400×) and (n) Epstein–Barr encoding region (EBER) gene test was negative. MRI: magnetic resonance imaging; IgG4: immunoglobulin G4; HPF: high-power field; CD3: cluster of differentiation.

Figure 3.

The black line graph shows the monthly serum IgG4 levels. A total of five pulse therapies (hormonal and immunosuppressive agents) were administered, with the treatment regimens indicated by blue boxes. IgG4: immunoglobulin G4.

Figure 4.

Orbital imaging of the lesion during hormone pulse therapy and after gamma knife surgery. (a–d) Orbital MRI during the third examination revealed a moderate mass (3.1 cm × 1.9 cm). The imaging characteristics were similar to those of the initial MRI, but the mass was smaller than that observed previously. (e–h) Orbital MRI during the fourth examination showed that the mass size was smaller before the second surgery. (i–l) Orbital MRI revealed a moderate mass (3.1 cm × 3.0 cm), indicating continued progression and (m–p) Orbital MRI at 6 months after gamma knife surgery revealed a significantly reduced mass (2.3 cm × 1.7 cm), showing substantial shrinkage compared with the preoperative size.

Discussion

IgG4-RD is an immune-mediated disorder characterized histopathologically by dense infiltration of lymphocytes and plasma cells, along with fibrosis. ¹ The term “IgG4-related disease” was first introduced by Aithal et al. in 2001, based on their observations among a group of patients with autoimmune pancreatitis and elevated serum IgG4 levels. ⁷ Subsequently, Yamamoto et al. identified similar pathological features in the enlarged lacrimal and salivary glands of a patient with Mikulicz disease, thereby establishing a link between IgG4+ plasma cells and orbital lacrimal gland lesions for the first time. ⁸ The diagnosis of IgG4-ROD requires a comprehensive evaluation with integration of clinical, serological, radiological, and pathological data.^9,10 Notably, obliterative phlebitis and fibrosis, which are common in systemic IgG4-RD, are less frequently observed in biopsies of IgG4-ROD, ³ where lymphocytic infiltration is a more prominent pathological feature. ¹¹ Additionally, only a few case reports have documented conjunctival, scleral, uveal, and choroidal involvement. ³ The presentation of IgG4-ROD as a diffuse retrobulbar mass is exceedingly rare. Vascular anomalies are typically classified into hemangiomas and vascular malformations. ¹² Orbital hemangiomas can be further categorized as superficial, deep, or mixed, depending on the lesion’s location. ¹³ In this case, a diagnosis of deep orbital hemangioma was made because the lesion was located behind the orbital septum and presented as a soft tissue mass in the orbit. Color Doppler ultrasonography revealed abundant blood flow within the lesion, displaying a mixed spectrum of arteriovenous blood flow. ¹³ MRI demonstrated a low signal on T1-weighted images and a high signal on T2-weighted images, with significant enhancement following contrast administration.^5,13 NTOH can arise from various underlying causes, such as vascular factors, sudden increases in cranial and orbital venous pressure, and bleeding diathesis.^12,14 Visual impairment is reported in up to two-thirds of NTOH patients, particularly those with posteriorly located hemorrhages. ⁵ In this case, the patient presented with a history of progressive left proptosis over the course of 1 week. Initial contrast-enhanced MRI demonstrated similar imaging characteristics, and the pathological findings confirmed the diagnosis of hemangioma. Therefore, considering a sudden increase in exophthalmos and a sudden decrease in visual acuity, we concluded that the patient already had self-identified orbital hemorrhage before both visits.

In this case, the preliminary pathological report initially identified an orbital hemangioma with a significant lymphocytic component in the left eye. However, the clinical manifestations and features did not fully align with a simple hemangioma. ¹¹ This discrepancy prompted further histological investigation using IHC staining, which provided a more definitive diagnosis and guided the treatment plan. A similar case was reported by Buthaina et al., ¹⁵ where orbital hemangioma was initially suspected; however, 4 years later, the diagnosis was revised to IgG4-ROD with ocular adnexal marginal zone lymphoma based on IHC findings. This highlights the importance of closely examining abundant lymphocytes using hematoxylin and eosin (HE) staining and the necessity of performing IHC when HE staining results are ambiguous.

For conventional orbital hemangiomas, surgical intervention and β-blocker medications are common and effective treatment options. ¹³ The first-line treatment for IgG4-RD is glucocorticoid therapy. ¹⁶ After surgical reduction of lesion volume, our treatment focus shifted to the management of IgG4-ROD. Our patient responded well to high-dose glucocorticoids initially, as indicated by clinical manifestations and blood tests. Unfortunately, follow-up imaging showed worsening of the condition when the glucocorticoid dose was reduced at 2 months. Previous reports indicate that GKRS can achieve nidus obliteration in 65%–85% of patients with arteriovenous malformations after a 3–5 year latency period in cerebral vascular anomalies. ¹⁷ In patients with refractory IgG4-ROD, combining local orbital radiation therapy with glucocorticoids (GCs) has been shown to stabilize clinical symptoms. ¹¹ Gamma rays are delivered using a frame-based gamma knife (GK) platform, which combines the precision of surgery with the advantages of radiation therapy. ¹⁸ We hypothesize that inflammatory factors associated with IgG4-ROD may induce the production of angiogenic mediators, while GK-induced endothelial damage alters the orbital microenvironment, inducing inflammatory and prothrombotic cascades ¹⁹ that inhibit orbital angiogenesis.

Vascular tumors are characterized by the abnormal proliferation of endothelial cells and aberrant blood vessels. ²⁰ Recent reports have clarified the vasculitic nature of IgG4-RD, as it can affect not only small and large blood vessels but also medium-sized vessels. ⁹ Although the current literature does not provide direct evidence of a relationship between these two conditions, both involve blood vessels, suggesting that the proliferation of hemangiomas may produce inflammatory factors that could trigger the development of IgG4-ROD-related vasculitis. Further studies are needed to explore the underlying mechanisms of this potential link.

In conclusion, the diagnosis of IgG4-ROD with a deep orbital hemangioma in the left orbit was made based on the patient’s medical history, clinical examination, pathological results, and treatment response. GKRS may offer a novel approach for controlling this disease. This rare case underscores the complexity and diversity of clinical manifestations associated with IgG4-ROD. For refractory and recurrent hemangiomas, immunohistochemistry and serological examinations are essential for differential diagnosis. Additionally, given the abundant lymphocytic infiltration observed in HE staining, further IHC analysis is recommended to confirm the diagnosis.