Orbital Rosai-Dorfman Disease Presenting as Optic Neuritis

A 55-years-old right-handed woman with hypothyroidism, controlled diabetes mellitus, anxiety, and history of sleeve gastroplasty presented with a one-month history of blurred vision of the left eye with retro-orbital soreness.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Orbital Rosai–Dorfman Disease Presenting as Optic Neuritis Harjot S. Virk, MPH, Kiarash Shahlaie, MD, PhD, Biswarathan Ramani, MD, Arie Perry, MD, Ruben Fragoso, MD, Joseph Tuscano, MD, Yin A. Liu, MD, PhD A 55-years-old right-handed woman with hypothyroidism, controlled diabetes mellitus, anxiety, and history of sleeve gastroplasty presented with a one-month history of blurred vision of the left eye with retro-orbital soreness. She described the blurred vision as “looking through a film.” She denied fevers, headaches, or systemic illness. She was initially evaluated by a local ophthalmologist and treated with intravenous methylprednisolone 1 gm daily for 5 days for presumed retrobulbar optic neuritis. Her vision returned to normal. Ophthalmologic examination revealed visual acuity of 20/20 in the right eye and 20/20 21 in the left eye. She had normal intraocular pressure, color vision, and visual fields to confrontation. There was a trace left relative afferent pupillary defect. The anterior segment showed no signs of infection or inflammation. Ocular motility was normal, and there was no misalignment. Her fundus examination was normal with healthy optic nerves and maculae in both eyes (Fig. 1A). Optical coherence tomography of the retinal nerve fiber layer and ganglion cell complex and automated visual field were normal bilaterally (Fig. 1B–D). MRI of the brain and orbits demonstrated a gadolinium-enhancing mass that involved the left lateral rectus and infraorbital optic nerve (Fig. 2A). The mass extended into the sphenoid wing and left middle cranial fossa with erosive intraosseous changes best seen on computed tomography (CT) images (Fig. 2A). Neurosurgery was consulted, and it was determined that surgery was necessary for tumor debulking and biopsy, and the patient underwent a left pterional craniotomy. Intraoperatively, frozen specimen School of Medicine (HSV), University of California, Davis, Sacramento, California; Department of Neurological Surgery (KS), University of California, Davis, Sacramento, California; Department of Pathology (BR, AP), University of California San Francisco, California; Department of Radiation Oncology (RF), University of California, Davis, Sacramento, California; Department of Medicine (JT), Division of Hematology/Oncology, University of California, Davis, Sacramento, California; and Department of Ophthalmology and Vision Science (YAL), University of California, Davis, Sacramento, California. The authors report no conflicts of interest. Address correspondence to Yin A. Liu, MD, PhD, UC Davis Eye Center, Department of Ophthalmology and Vision Science, University of California, Davis, 4860 Y Street, Suite 2400, Sacramento, CA 95817; E-mail: [e-mail] Virk et al: J Neuro-Ophthalmol 2022; 42: e293-e296 analysis suggested an inflammatory rather than neoplastic process. Therefore, only the extraorbital component of the lesion was resected. Histopathological analysis of the permanent section demonstrated a fibroinflammatory process involving the bone with abundant plasma cells with S100-positive histiocytes demonstrating emperipolesis, resulting in a final diagnosis of Rosai– Dorfman disease (RDD) (Fig. 2B). After debulking, the patient received oral prednisone for 16 weeks, starting at 80 mg per day tapered down by 20 mg every 2 weeks until she was receiving 40 mg daily. After 5 weeks, the dose was tapered down by 10 mg every 2 weeks until the steroids were discontinued. However, imaging showed no clear improvement in the intraorbital tumor. She then received 2 cycles of chemotherapy with 0.15 mg/kg cladribine daily for 5 days. Repeat imaging demonstrated no change in the intraorbital mass (Fig. 2C). A positron emission tomography scan also confirmed the presence of soft tissue mass in the orbit with no other findings related to RDD. The intracranial tumor did not recur, and her visual function remained normal, although the patient experienced intermittent headaches. The patient then underwent radiation therapy to a total dose of 30 Gy given in 2 Gy fractions. MRI after radiation therapy again showed a stable intraorbital mass. The patient and provider decided at this point to monitor the mass with serial MRI scans. DISCUSSION RDD represents a non-Langerhans cell histiocytosis and is also known as sinus histiocytosis with massive lymphadenopathy. Although previously believed to be a reactive histiocytosis, more recent studies have uncovered clonal MAP kinase alterations, including BRAF V600E mutations leading to a growing consensus that this is a neoplastic process (1). Constitutional symptoms such as fever, malaise, and night sweats are the most common, but extranodal disease can present with site-specific symptoms (2). Extranodal involvement occurs in over 40% of cases, with ophthalmic involvement in up to 11% of cases (2). For orbital cases, symptoms such as proptosis and vision changes are commonly present and systemic manifestations are less likely when compared with ocular disease (3,4). e293 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Findings on ophthalmologic evaluation of the patient. Fundus photographs (A), optical coherence tomography of the retinal nerve fiber layer thickness (B), ganglion cell layer and internal plexiform layer thickness (C), and automated visual field 24-2 (D) are all within normal limits on initial examination in both eyes. RDD must be differentiated on MRI from other dural masses, especially meningioma. Both are isointense to cortex on T1 sequences, avidly enhance with contrast, and demonstrate a dural tail (5). However, bone involvement typically differs with hyperostosis more common in meningioma and bone infiltration characteristic of RDD (Fig. 2A) (5). Definitive diagnosis of RDD is made pathologically by assessing for emperipolesis (2). Immunohistochemical staining with S100, CD163, CD68, and CD1a can aid in establishing RDD as the diagnosis by demonstrating histiocytes that are S100, CD163, and CD68 positive and CD1a negative (Fig. 2B) (2). S100 positivity distinguishes RDD histiocytes from normal sinus histiocytes, and CD68-positive staining is a feature of phagocytic histiocytes. CD163 positivity is seen in e294 monocytic and histiocytic cell lines which may be associated with RDD, histiocytic sarcoma, and Langerhans cell histiocytosis (6). However, Langerhans cell histiocytosis has CD1a-positive cells, whereas histiocytes in RDD are CD1a negative (6). Despite only half of RDD cases requiring treatment, over 90% of cases with orbital involvement require intervention (3). Owing to the rarity of the disease and lack of consistently efficacious therapies, there are no definitive treatment guidelines for RDD. Steroids, cytotoxic agents, radiation therapy, and surgery have all been used to treat RDD with variable success. Steroid therapy is often favored as first-line therapy for systemic disease and asymptomatic cases (2). Recommended corticosteroid therapy regimens are prednisone 40–70 mg (or 1 Virk et al: J Neuro-Ophthalmol 2022; 42: e293-e296 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence mg/kg) daily or dexamethasone 8–20 mg daily, both followed by taper (2). However, unifocal extranodal disease is best treated surgically, and resection is indicated for CNS, head, and neck cases that result in neurological symptoms or airway obstruction (2,7). Both radiation and chemotherapy are options for residual, recurrent, or symptomatic disease after surgery. Chemotherapy regimens that have been used for treatment of RDD include 20 mg/m2 per week of methotrexate either alone or in combination with 50 mg/m2 of 6-mercaptopurine (6MP) (2). Cladribine doses of 2.1–5 mg/m2 and clofarabine doses of 25 mg/m2 daily for 5 days every 28 days over 6 months have also been efficacious (2). Although there is no consensus on doses or modality, 20–50 Gy of radiation therapy has shown to be beneficial in orbital bone disease. RDD does not generally carry a poor prognosis, although some studies have shown mortality of 7%– 12% attributed to the disease (2). In a review of 6 cases of CNS disease, 5 achieved stable disease through some combination of surgery, chemotherapy, and radiation therapy, and one patient had progressive disease that was managed palliatively (7). Follow-up in these cases varied greatly (7 months–10 years), and optimal length of follow-up is unclear (7). We report a case of orbital RDD with intracranial involvement that initially presented with optic neuritis– like symptoms and responded to intravenous steroids with complete resolution of partial visual loss. However, the intraorbital mass was refractory to steroids, chemotherapy, and radiation. At this stage, our patient seems to have stable disease and will continue to be monitored with serial imaging and ophthalmological examinations. This case demonstrates the importance of considering RDD when evaluating monocular partial vision loss, especially when imaging shows a dural mass. Further research is needed to understand optimal treatment and management of patients with orbital RDD. FIG. 2. Characteristics of Rosai–Dorfman disease on computed tomography (CT) imaging, MRI, and immunohistochemistry staining. T1 axial and coronal MRI images show homogenous, noncalcified, enhancing mass with infiltration of the greater wing of the sphenoid (A, top left, red arrowhead) and intraorbital mass (A, top left, blue arrowhead, and bottom left, blue arrowhead) encasing the optic nerve without involvement of optic chiasm (A, bottom right, white arrowhead). CT image shows a lytic lesion (A, top right, white arrow) in the greater wing of sphenoid without reactive hyperostosis. T1 axial and coronal MRI images 2 months postoperative (C, top Virk et al: J Neuro-Ophthalmol 2022; 42: e293-e296 images) and after 2 cycles of cladribine (C, bottom images) demonstrating a persistent orbital mass (C, red arrowheads) and postsurgical changes (C, blue arrowheads). Hematoxylin and eosin–stained paraffin sections (left, B: low power and middle, B: high power) demonstrate a mixed inflammatory infiltrate arranged in nodular clusters in a fibrotic background (white arrow, B). Within these clusters are collections of atypical histiocytes that exhibit abundant foamy cytoplasm and features suggestive of emperipolesis (black arrows, B). An S100 immunohistochemical stain (right, B) is positive in the atypical histiocytes and highlights emperipolesis (red arrow, B). CD68 (bottom left, B) and CD163 (bottom middle, B) immunohistochemical stains are also positive while CD1a (bottom right, B) stain is negative. e295 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: H. S. Virk, K. Shahlaie, and Y. A. Liu; b. Acquisition of data: H. S. Virk, K. Shahlaie, B. Ramani, A. Perry, R. Fragoso, J. Tuscano, and Y. A. Liu; c. Analysis and interpretation of data: H. S. Virk, K. Shahlaie, B. Ramani, A. Perry, R. Fragoso, J. Tuscano, and Y. A. Liu. Category 2: a. Drafting the manuscript: H. S. Virk, K. Shahlaie, B. Ramani, A. Perry, R. Fragoso, J. Tuscano, and Y. A. Liu; b. Revising it for intellectual content: H. Virk, K. Shahlaie, B. Ramani, A. Perry, R. Fragoso, J. Tuscano, and Y. A. Liu. Category 3: a. Final approval of the completed manuscript: H. S. Virk, K. Shahlaie, B. Ramani, A. Perry, R. Fragoso, J. Tuscano, and Y. A. Liu. 3. 4. 5. 6. REFERENCES 1. Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020;73:697–705. 2. 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RosaiDorfman disease of the central nervous system: report of 6 cases and review of the literature. Medicine (Baltimore). 2014;93:165–175. Virk et al: J Neuro-Ophthalmol 2022; 42: e293-e296 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.