Novel Diagnosis of the Diffuse Variant of Infantile Orbital Fibromatosis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Novel Diagnosis of the Diffuse Variant of Infantile Orbital Fibromatosis Kanwal S. Matharu, MD, Adam R. Sweeney, MD, Patricia Chévez-Barrios, MD, Jane C. Edmond, MD, Douglas P. Marx, MD, Richard C. Allen, MD, PhD, Veeral S. Shah, MD, PhD FIG. 1. Serial neuroimaging at 3-year follow-up show stable enlarged muscles in the right orbit. Initial presenting MRI T1weighted coronal and axial (A, B) demonstrate enhancement of enlarged extraocular muscles, but are hypointense on T2weighted images (C) suggestive of fibromatosis. D–F. Follow-up imaging at 3 years show minimal interval change and stability in the disease. Department of Ophthalmology (KSM, ARS, JCE, DPM, RCA, VSS), Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; Department of Ophthalmology (KSM, ARS, PC-B, JCE, DPM, RCA, VSS), Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; Departments of Pathology and Laboratory Medicine and Ophthalmology (PC-B), Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine and Ophthalmology (PC-B), Houston Methodist, Houston, Texas; Department of Ophthalmology (JCE), Wong Eye Institute, Dell Medical School, Austin, Texas; Department of Ophthalmology (DPM), Moran Eye Center, University of Utah, Salt Lake City, Utah; and Department of Ophthalmology (VSS), Cincinnati Eye Institute, University of Cincinnati, Cincinnati, Ohio. The authors report no conflicts of interest. Address correspondence to Veeral S. Shah, MD, PhD, Cincinnati Children’s Hospital Medical Center, Abrahamson Pediatric Eye Institute/Division of Pediatric Ophthalmology, 3333 Burnet Avenue, MLC 7003, Cincinnati, OH 45229-3039; E-mail: [e-mail] e316 A 23-month-old man was referred for a history of painless, progressive proptosis and motility deficits of the right eye (right eye) for 1 year. There was no history of trauma or malignancy. The patient had an unremarkable birth, medical, and family history. On ocular examination, he had fix and follow vision in both eyes (both eyes) without a relative afferent pupillary defect. External examination revealed axial proptosis in the right eye. Anterior segment and dilated fundus examination, including the optic nerves, were normal in both eyes. Intraocular pressure was 16 mm Hg in the right eye and 18 mm Hg in the left eye (left eye). Ocular motility in the right eye was moderately restricted in all fields of gaze, but full in the left eye with orthophoric alignment in a primary position. Matharu et al: J Neuro-Ophthalmol 2021; 41: e316-e318 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Four-year follow-up demonstrated no signs of optic neuropathy despite continued abutment of IOF in the right orbit. Optic nerve fundus photographs and OCT of the peripapillary retinal nerve fiber layer showed of no signs of optic neuropathy in the affected right eye (A, B). The unaffected left eye is shown with mild pseudopapilledema changes but is otherwise normal (C, D). MRI demonstrated enlargement of the medial, inferior, and lateral rectus and the superior oblique muscles in the right orbit; straightening of the right optic nerve; and axial proptosis in the right eye without significant globe deformation (Fig. 1). Laboratory workup was unrevealing with normal thyroid panel, IgG panel, lysozyme, angiotensin-converting enzyme, and complete blood count. An anterior orbitotomy and incisional biopsy of the enlarged, sclerotic right lateral rectus muscle predominantly demonstrated fibrosis dissecting muscle and infiltrating fat with a bland spindle cell proliferation. Masson’s trichrome staining confirmed the infiltrative and dense nature of the fibrosis between muscle fibers. To exclude a low-grade spindle cell tumor, immunohistochemistry was performed. Tissue biopsy was stained negative for desmin (rhabdomyosarcoma and other muscle tumors), smooth muscle actin (leiomyoma and myofibroblastic lesions and tumors), CD68 (histiocytic lesions), and S100 (neural crest tumors and melanoma). Vimentin and CD34 were diffusely positive, whereas beta-catenin was focally positive (Fig. 3). The proliferation rate was ,1% using Ki67 (MIB1), and Matharu et al: J Neuro-Ophthalmol 2021; 41: e316-e318 no mitoses were found. A complete histopathology review by multiple pathologists ruled out other etiologies of infantile orbital spindle cell conditions including desmoid variant of infantile orbital fibromatosis (IOF) (Fig. 3). Given the benign tissue histopathology and complete ocular examination including age-appropriate vision, a healthy optic nerve, and normal alignment, the patient was monitored for surveillance with orbital neuroimaging and ocular examinations for vision development. At the 3year follow-up, he had developed 20/30 in the right eye and 20/25 in the left eye vision with normal-appearing optic nerves. His overall motility had worsened marginally with a small-angle right exotropia. MRI demonstrated stable findings of the right extraocular muscles and optic nerve with compensatory enlargement of the right orbit (Fig. 1). Although he had good vision and normal optic nerve by examination and optical coherence tomography (OCT) testing at the 4-year visit, he underwent orbital decompression surgery for increasing proptosis (Fig. 2). Tissue biopsy demonstrated normal cytogenetics; an absence of dysplastic, malignant features on histopathology; and fibrocytic nature on electron microscopy. Thus, we present the clinical presentation, natural history, neuroimaging, and histopathology of a novel diagnosis: the diffuse-type IOF. Here, we describe a 2-year-old man with 1 year of painless, progressive proptosis, ophthalmoplegia of the right eye, stable neuroimaging involving multiple muscles without a focal tumor, and histopathology inconsistent with any other previously described disease (Fig. 3). Without evidence-based strategies regarding management of the diffuse type of infantile fibromatosis, we considered the desmoid subtype of IOF as a guide for molecular mechanism, etiology, and management. IOF is a rare, fibrotic, spindle cell infiltrative disease that can involve the extraocular muscles and periorbital tissue and is characterized by a spectrum of clinical findings, neuroimaging, and pathology. This disease has been described in 5 female and 3 male children less than 4 years old, all of whom demonstrated a locally aggressive, focal tumor with infiltration of the orbit and muscles, consistent with the desmoid subtype variant of IOF (1–4). In the desmoid type, dysregulation of the Wnt pathway leads to increased beta-catenin and upregulation of downstream transcription factors, resulting in diffuse beta-catenin staining microscopically and fibrosis macroscopically (5). Multiple etiologies have been proposed, including estrogen receptor dysregulation, genetic predisposition, and trauma (3). Practice patterns have shifted from resection to observation of IOF tumors given their low proliferation potential, morbidity of surgery, and the recurrence rate. This is in keeping with our initial approach: surveillance with neuroimaging and ocular examinations with close monitoring to prevent vision-threatening sequelae (including compressive optic neuropathy and strabismic amblyopia). In 4 years of follow-up, there were no apparent signs of the optic nerve damage or neuropathy in the right eye. The goal of current e317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. Histopathology shows dense and diffuse fibrosis infiltrating muscle and fat. A. The muscle (M) fibers are dissected by dense eosinophilic fibrosis and few fibroblasts. B. There are areas of solid eosinophilic fibrosis with cellular basophilic proliferation. C. The fibrosis and fibroblastic proliferation infiltrates fat (F) (hematoxylin and eosin stain; original magnification 40X). D. Trichrome Masson stain demonstrates the muscle fibers in red dissected by dense fibrosis in blue (trichrome masson stain; original magnification 40X). E. Diffuse staining with CD34 is seen (Immunohistochemistry using CD34 antibody, DAB chromogen; original magnification 40X). F. Focal and weak staining with beta-catenin is seen (immunohistochemistry using beta-catenin antibody, DAB chromogen; original magnification 40X). treatment is to monitor for stability and optimal vision development, specifically to prevent amblyopia given his age. In summary, we present a novel diagnosis and natural history of the diffuse-type of IOF. For patients with similar presentations, we recommend orbital neuroimaging, incisional biopsy, and histopathology analysis for definitive diagnosis. Surveillance with serial orbital imaging and ocular examination are the mainstay for management of IOF, especially in young, preverbal children for optimal vision development. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. C. Allen, P. Chévez-Barrios, and V. S. Shah; b. Acquisition of data: D. P. Marx, J. C. Edmond, R. C. Allen, K. S. Matharu, A. R. Sweeney, and V. S. Shah; c. Analysis and interpretation of data: K. S. Matharu, D. P. Marx, J. C. Edmond, P. Chévez-Barrios, R. C. Allen, and V. S. Shah. Category 2: a. Drafting the manuscript: K. S. Matharu, A. R. Sweeney, D. P. Marx, J. C. Edmond, R. C. Allen, and V. S. Shah; b. Revising it for intellectual e318 content: V. S. Shah, R. C. Allen, and P. Chévez-Barrios. Category 3: a. Final approval of the completed manuscript: V. S. Shah, R. C. Allen, and P. Chévez-Barrios. REFERENCES 1. Hidayat AA, Font RL. Juvenile fibromatosis of the periorbital region and eyelid. A clinicopathologic study of six cases. Arch Ophthalmol. 1980;98:280–285. 2. Hayashi K, Katori N, Otsuki Y, Ohno-Matsui K. Clinicopathological study of three cases of infantile fibromatosis of the orbit. Int Ophthalmol. 2014;34:1097–1106. 3. 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