Eosinophilic Angiocentric Fibrosis in Bilateral Upper Eyelid Conjunctivas: A First Case Report.

BACKGROUND Eosinophilic angiocentric fibrosis (EAF) is an extremely rare disease with characteristic histopathological findings of fibrotic onion-skin appearance and eosinophils. The lesion primarily affects the nasal cavity, paranasal sinus, and orbit. Although there have been approximately 78 cases of EAF reported in the literature to date, no cases of EAF in the eyelid conjunctiva have ever been reported. CASE REPORT Herein, we describe the case of a 55-year-old Japanese woman with a history of eosinophilic sinusitis and EAF in bilateral upper eyelid conjunctivas who underwent surgical resection of the affected tissue. Histopathological examination revealed collagen bundles winding around the vessels in an onion-skin pattern, and the presence of eosinophils, lymphocytes, and plasma cells. CONCLUSIONS We describe the first reported case of EAF in bilateral upper eyelid conjunctivas. It can be successfully treated by surgical resection, and with no recurrence within 6 months postoperatively.

Background

Eosinophilic angiocentric fibrosis (EAF) is an uncommon clinical condition that usually affects the nasal cavity, paranasal sinus, orbit, and, in rarer cases, it can affect the lacrimal gland, respiratory tract, retro orbit, and gingiva [1-5]. It was first described by Holmes and Panje [6] in 1983 as “intranasal granuloma faciale”. The histopathology of EAF typically involves concentric fibrosis surrounding arterioles, and the presence of numerous eosinophils [2]. In 1985, Roberts and McCann [7] described 3 similar cases and coined the histologically descriptive name [2]. There is no established treatment for EAF, but commonly used treatments include surgical resection, systemic and topical corticosteroids, and a combination of these 2 methods [2]. It has also been reported that rituximab improved serology test results and the lesions in a few cases of EAF.

To date, 78 cases of EAF have been reported in the scientific literature worldwide, including 61 in the nasal cavity, 23 in the paranasal sinus, 13 in the orbit, 4 in the respiratory tract, 3 in the lacrimal gland, 1 in the gingiva, and 1 behind the orbit [2,8-14]. Notably, however, no cases of EAF in the eyelid conjunctiva have ever been reported. Herein, we describe a case of bilateral EAF involving the upper eyelid conjunctivas.

Case Report

The patient was a 55-year-old Japanese woman with a history of sinusitis who had undergone endoscopic resection 2 years prior and was histologically diagnosed with eosinophilic sinusitis. Six months later, she exhibited bilateral upper eyelid conjunctival swelling without pain. The lesions were resistant to treatment with 0.05% epinastine hydrochloride ophthalmic solution (ALESION®, Santen Pharmaceutical, Osaka, Japan), 0.1% fluorometholone ophthalmic suspension (Flumetholon®, Santen Pharmaceutical, Osaka, Japan), and 0.1% tacrolimus ophthalmic suspension (TALYMUS®, Senju Pharmaceutical Co., Osaka, Japan) 4 times a day, so she was referred to our outpatient clinic. The preoperative appearances of the conjunctival upper eyelids are shown in Figure 1.

Figure 1.

Preoperative upper eyelid conjunctiva findings. (A) Right and (B) left upper eyelid conjunctiva swelling involving pale lesions.

The patient had a history of eosinophilic sinusitis but no history of drug allergies. The results of routine blood examinations and blood biochemistry were all within normal ranges. Levels of total IgG and other subtypes were normal, with the exception of serum IgG4, which was 179 mg/dL (normal range 11–121 mg/dL). Other autoimmune screening tests, including anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody, anti-PR3 antibody, anti-myeloperoxidase antibody, and antinuclear body, were all negative (Table 1). Magnetic resonance imaging of the head did not reveal any major complications or swelling in the lacrimal gland, salivary gland, or infraorbital nerve (Figure 2).

Table 1.

Blood examination results.

Tests	Results	Units	Reference range
WBC	5.5	×103/μL	3.0–7.8
RBC	3.95	×106/μL	3.53–4.66
Plt	282	×103/μL	138–309
Bun	12.8	mg/dL	7–24
Cr	0.70	mg/dL	≤0.70
Na	141	mEq/L	135–147
CL	105	mEq/L	98–108
AST	20	U/L	8–38
ALT	13	U/L	4–44
CRP	0.09	mg/dL	≤0.3
Free T3	2.4	pg/mL	1.71–3.71
Free T4	1.3	ng/dL	0.70–1.48
TSH	1.51	μIU/mL	0.36–3.67
IgA	261	mg/dL	110–410
IgG	1241	mg/dL	870–1700
IgG2	542	mg/dL	239–838
IgG4	179	mg/dL	11–121
IgM	73	mg/dL	52–270
C3	118	U/mL	80–140
C4	35	U/mL	17–45
RF	11	IU/mL	≤15
Anti-SSA antibody	(–)
Anti-SSB antibody	(–)
C-ANCA	(–)
P-ANCA	(–)
ANA	(–)
C-ANCA	(–)
P-ANCA	(–)
ANA	(–)

RF – rheumathoid factor; SSA – Sjogren’s syndrome A; SSB – Sjogren’s syndrome B; C-ANCA – anti-PR3 antibody; P-ANCA – anti-myeloperoxidase antibody; ANA – anti-nuclear antibody.

Figure 2.

Magnetic resonance imaging (MRI) of the head, indicating that the lacrimal gland, salivary gland, and infraorbital nerve were intact.

Treatment and follow-up

The patient underwent surgical resection without complications (Figure 3) and was treated with fluorometholone eye drop 4 times a day. Her postoperative course was uneventful. She was followed up every 2 months for approximately 6 months, during which there was no evidence of recurrence of the disease.

Figure 3.

Postoperative observations in the upper eyelid conjunctivas. (A) Right and (B) left upper eyelid conjunctivas 2 months after surgery. Fibrotic lesions were surgically resected in both eyes.

Pathologic findings

The specimens resected from both eyelid conjunctivas were characterized by hard lesions with a homogeneous yellowish-white solid and a macroscopically rough surface. Histological examination of the conjunctival mucosa showed marked chronic inflammation of submucosa and stromal fibrosis (Figure 4). The inflammatory infiltrate was composed of mature lymphocytes, plasma cells, and numerous eosinophils (Figure 5A). The conjunctival epithelium was characterized by the irregular growth of limbal epithelial cells due to inflammation. The stromal fibrosis showed concentric lamellar deposition of collagen/onion-skin-like appearance with scattered eosinophils around the blood vessels and focal storiform fibrosis (Figure 5B). There was no true granulomatous reaction, cytologic atypia, or mitotic activity. Immunohistochemical staining for IgG4 showed that 68 plasma cells were positive for the IgG4/high-power field, and the IgG4/IgG ratio was 45% (Patholoscope, Mitani Co.). These findings are consistent with IgG4-related diseases, which increase the number of IgG4-positive plasma cells and the IgG4/IgG ratio (Table 2). These histological features, such as eosinophilic vasculitis and angiocentric fibrosis with the onion-skin pattern, led us to diagnose this case as eosinophilic angiocentric fibrosis. In addition, fibrosis was pronounced in the left-side lesions, suggesting a more advanced stage.

Figure 4.

Histopathology image of a tissue sample from the upper conjunctiva of the left eye (hematoxylin and eosin staining, ×40 magnification). Infiltration of numerous inflammatory cells and fibrous connective tissue are evident.

Figure 5.

Histopathology images of tissue samples from the upper conjunctiva of the left eye (hematoxylin and eosin staining, ×200 magnification). (A) Inflammatory infiltration composed of mature eosinophils, lymphocytes, and plasma cells. (B) The conjunctival epithelium was characterized by the irregular growth of limbal epithelial cells due to inflammation. The stromal fibrosis showed concentric lamellar deposition of collagen/onion-skin-like appearance with scattered eosinophils around the blood vessels and focal storiform fibrosis.

Table 2.

Diagnostic criteria.

Diagnosis of immunoglobulin G4 (IgG4)-related diseases
1. Clinical findings
Prominent or nodule-like lesion
2. Serological findings
IgG4 ≥135 mg/dL
3. Histopathological findings
a. Infiltration with lymphocytes and plasma cells
b. IgG4-positive plasma cells ≥10/high power field
c. Lesional IgG4: IgG ratio ≥40%

Discussion

EAF is considered a benign disorder, and the diagnosis of EAF is based on histopathological findings characterized by inflammatory infiltration of eosinophils, fibrotic bundles around vessels, and an onion-skin pattern accompanied by fibrotic stroma [7,15]. These characteristic changes were evident in the present case. Seventy-eight cases of EAF have been described to date [2,8-14], and while the involvement of “neoplasms” or “inflammatory lesions” has been variously described, the exact pathology of EAF remains unclear. In the present case, fibrous inflammatory lesions were observed in the absence of any indications of malignancy.

During the early phase of EAF, the lesion consists of eosinophilic vasculitis with a mixture of lymphocytes and plasma cells. Inflammatory infiltration gradually becomes hypocellular, with increasing fibrosis [15]. The late phase of EAF is characterized by dense fibrous thickening of the stroma and perivascular onion-skin fibrotic changes [15]. Histopathological findings typical of both early phase (Figure 5A) and late phase (Figure 5B) EAF were observed in the present patient.

Though there is currently no consensus on the etiology of EAF. In 2011, Deshpande et al. [16] concluded that it belongs to the spectrum of IgG4-related diseases, which are characterized by a “tumefactive” or nodule-like lesion, large numbers of IgG4 positive plasma cells, and an elevated IgG4-positive to total IgG-positive cell ratio [2,8,16,17]. Criteria for the diagnosis of IgG4-related diseases are summarized in Table 2, and all findings in the present patient were concordant with items 1–3 therein. Prominent lesions in bilateral upper eyelids, swelling, and raised serum IgG4 (179 mg/dL) were observed. Histopathological examinations revealed lymphocytes and plasma cell infiltration, increased IgG4-positive plasma cells, and a 45% proportion of IgG4-positive cells.

The differential diagnosis of EAF includes the consideration of Churg-Strauss syndrome, granulomatosis with polyangiitis, Kimura’s disease, Sjogren’s syndrome, and sarcoidosis [2,3]. Churg-Strauss syndrome and granulomatosis with polyangiitis are reactive conditions characterized by eosinophilic infiltration with systemic symptoms.

The lack of histologic features such as giant cells and necrosis aids in distinguishing EAF [2]. In this case, a negative blood test for ANCA helps exclude these diagnoses. Kimura’s disease reveals histologically inflammatory cells and fibrosis; however, it shows a prominent germinal center, not fibrotic stroma, around vessels. Sjogren’s syndrome is an autoimmune disease that affects the body’s moisture-producing glands. Primary symptoms are dry mouth and dry eyes. Sarcoidosis is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomas. The disease usually begins in the lungs, skin, or lymph nodes and sometimes affects the eyes. However, the lack of systemic signs, negative auto-immune serology, and nonspecific MRI help exclude Sjogren’s syndrome and sarcoidosis. Furthermore, the well-developed angiocentric fibrosis in our case is highly characteristic of EAF.

No definitive treatment has been identified, but most cases are treated with surgical resection alone or combined with medication [1,18-21]. In 62% of surgeries, patients underwent complete resection, with a recurrence rate of 20% [10]. The recurrence rate is high and multiple excisions are frequently required [1,2]. The present case was considered IgG4-related disease, which was steroid-reactive, so we provided therapy with triamcinolone acetonide subconjunctival injection and 0.1% fluorometholone eye drop 4 times a day after surgery. The eye drops were gradually reduced, and she has been symptom-free for half a year after the resection.

Although some studies reported that systemic rituximab administration was effective in treating EAF [22,23], we used only topically in this case, which had no sign of general symptoms.

Conclusions

Herein, we have described the first reported case of EAF involving bilateral upper eyelid conjunctivas. Surgical resection was successful, and no recurrence has occurred within 6 months after surgery.