A 79-year-old woman was referred to our institution with a 1-year history of tearing, blurry vision, pain, photophobia, and redness in her right eye. Past medical history was significant for breast cancer, which required right lumpectomy 14 years prior and left lumpectomy plus radiation that was completed about 1 year prior to referral. The patient’s symptoms in the right eye had begun about 1 month following the completion of the radiation treatment for breast cancer, at which point she was diagnosed with nodular scleritis inferotemporally in the right eye, and she was found to have elevated perinuclear accentuated anti-neutrophil cytoplasmic antibodies (p-ANCA), leading to suspicion for granulomatosis with polyangiitis. She was managed by multiple ophthalmologists and rheumatologists. Medical history also included insulin-dependent diabetes, hypertension, hyperlipidemia, anemia, and colon cancer about 16 years prior. There was a history of maxillary and sphenoid sinusitis, for which the patient had right mastoid surgery, as well as a history of bilateral ear tubes. The patient also had, at the time of presentation, bilateral renal oncocytomas treated with cryoablation, but renal function was normal. Past ocular history included open-angle glaucoma initially well-controlled with topical therapy alone but later exacerbated by an inflammatory/corticosteroid-induced component in the right eye. Prior to referral, the patient had been treated with oral prednisone, with good response, but experienced recurrences whenever the dose was tapered. She had also been treated with cyclophosphamide and indomethacin but had a history of poor response to azathioprine. Upon referral to our institution, best corrected visual acuity (BCVA) was 20/80 in the right eye. Slit-lamp examination demonstrated 360° of conjunctival and scleral injection, nodules in the temporal sclera, and 1+ nuclear sclerotic cataract. Dilated fundus examination and B-scan ultrasound showed panuveitis and serous retinal detachment associated with subretinal fluid (Fig. ). A “T” sign was also noted on ultrasound, consistent with posterior scleritis. Left eye exam was unremarkable. The differential diagnosis included inflammatory sclero-uveitis and intraocular lymphoma but favoring a diagnosis of inflammatory anterior/posterior scleritis and uveitis. An extensive work-up for sclero-uveitis was only positive for p-ANCA with a titer of >1:640 (normal <1:10). Pertinent negatives included rheumatoid factor, rapid plasma reagin, fluorescent treponemal antibody, and angiotensin converting enzyme. The leading diagnosis was granulomatosis with polyangiitis, and the patient was treated with oral prednisone, cyclophosphamide, and indomethacin and showed clinical improvement, with vision improving to 20/40.\nNine months later, our patient was referred again with an exacerbation of her inflammation after cataract surgery in the right eye (performed at an outside institution). Her BCVA was 20/200. Slit-lamp examination showed mild scleral injection with a fibrotic-appearing lesion adherent to the medial sclera. Dilated fundus examination demonstrated chorioretinal scars with subretinal fibrosis and pale optic nerve. The infiltrative fibrotic lesion on the sclera was biopsied, and histologic examination revealed mixed chronic inflammatory infiltrate with fibrosis consistent with orbital inflammatory pseudotumor (Fig. b–d). Although no actively necrotizing vasculitis was seen, a portion of the inflammation exhibited a vasculo-centric pattern, with hyalinization of vessels, raising the possibility that these findings represented the late stage of a vasculitic process, and accordingly, granulomatosis with polyangiitis remained in the differential diagnosis (Fig. b, c).\nTreatment subsequently included methotrexate and infliximab infusions, but the patient continued to have recurrent eye pain and eventually developed a blind, painful right eye with end-stage glaucoma and persistent vitritis, besides evidence of optic nerve sheath inflammation on imaging, leading to an enucleation. The histopathology of the globe showed necrotizing and fibrotic granulomatous scleritis and granulomatous panuveitis (Fig. ). Of note, microbial stains were negative. Chronic optic neuritis was also noted, with optic cupping and atrophy (Fig. a, e). There was serous detachment of the retina with subretinal protein, correlating with the clinical appearance (Fig. a). The retina exhibited severe atrophy, with chronic vasculitis seen in some of the retinal vessels (Fig. f), and a neovascular epiretinal membrane was appreciated overlying the pars plana. There were no atypical lymphocytes or any evidence of lymphoma on immunohistochemistry, with T cells (CD3-positive) far outnumbering the B cells (CD20-positive), and with in situ hybridization demonstrating a relatively even mixture of kappa- and lambda-positive plasma cells (not shown). Many of the plasma cells stained positive with IgG4 (Fig. g), i.e., about 70 per high-power field, comprising over 50 % of the total plasma cell population. (The total plasma cells were assessed with CD138 immunostain, not shown.) The previous episcleral/orbital biopsy was then retrospectively also stained with IgG4 immunostain, which likewise revealed positivity in >50 % of the plasma cell population (Fig. d). (Serum IgG4 was not obtained.)
A 76-year old man with a history of bilateral lacrimal gland masses and an otherwise unremarkable ocular examination underwent left orbital biopsy at another institution. Clinical suspicion was high for possible lymphoma due to the additional presence of cervical and axillary lymphadenopathy. The histologic diagnosis at that time was reactive lymphoid hyperplasia with fibrosis. Immunohistochemistry, kappa/lambda in situ hybridization, and flow cytometry were negative for lymphoma. The patient was lost to follow-up without any further work-up. He presented a year later due to recurrence of orbital inflammation, at which point the surgeon requested histologic work-up for IgG4-related disease. The slides from the prior orbital biopsy were requested and reviewed, showing lymphoid follicles with intervening bands of fibrosis and mixed chronic inflammatory cells. The tissue block was also received, and additional sections were cut for CD138 and IgG4 immunostaining. There were at least 150–180 IgG4-positive plasma cells per high-power field, comprising over 40 % of the total plasma cell population (as assessed by CD138). (Serum IgG4 was not obtained.) This was considered consistent with IgG4-associated orbital inflammatory pseudotumor with sclerosing features. The patient was initially treated with prednisone and then transitioned to intravenous rituximab as first-line therapy and had an excellent response with no recurrence at 2 years following therapy.