Title | Gorham-Stout Disease Presenting as Acute Unilateral Proptosis |
Creator | Inna G. Stroh, MD, PhD; Lilangi S. Ediriwickrema, MD; Neil R. Miller, MD |
Affiliation | Division of Neuro-Ophthalmology, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland |
Abstract | Gorham-Stout disease (GSD) is a rare angiomatous disorder characterized by osteolysis. We report the case of a 66-year-old woman who developed sudden left eye proptosis and facial pain. Neuroimaging demonstrated a destructive mass involving the roof and lateral wall of the left orbit with adjacent abnormal orbital soft tissue. An initial biopsy of the soft tissue was nondiagnostic; however, transcranial biopsy of the orbital roof revealed an intraosseous cavernous angioma, with infiltration of orbital fat by angiomatous tissue. Despite resection of the orbital roof and lateral wall, the orbital lesion continued to expand, leading to signs of a compressive optic neuropathy. The patient then reported severe back pain, prompting imaging that demonstrated disseminated bony involvement of the axial skeleton, eventually leading to the diagnosis of GSD. The patient was treated with a bisphosphonate and a vascular endothelial growth factor inhibitor with stabilization of disease. |
Subject | Gorham-Stout Disease; Acute Unilateral Proptosis |
OCR Text | Show Clinical Observation Gorham-Stout Disease Presenting as Acute Unilateral Proptosis Inna G. Stroh, MD, PhD, Lilangi S. Ediriwickrema, MD, Neil R. Miller, MD Abstract: Gorham-Stout disease (GSD) is a rare angiomatous disorder characterized by osteolysis. We report the case of a 66-year-old woman who developed sudden left eye proptosis and facial pain. Neuroimaging demonstrated a destructive mass involving the roof and lateral wall of the left orbit with adjacent abnormal orbital soft tissue. An initial biopsy of the soft tissue was nondiagnostic; however, transcranial biopsy of the orbital roof revealed an intraosseous cavernous angioma, with infiltration of orbital fat by angiomatous tissue. Despite resection of the orbital roof and lateral wall, the orbital lesion continued to expand, leading to signs of a compressive optic neuropathy. The patient then reported severe back pain, prompting imaging that demonstrated disseminated bony involvement of the axial skeleton, eventually leading to the diagnosis of GSD. The patient was treated with a bisphosphonate and a vascular endothelial growth factor inhibitor with stabilization of disease. Journal of Neuro-Ophthalmology 2018;38:70-74 doi: 10.1097/WNO.0000000000000569 © 2017 by North American Neuro-Ophthalmology Society G orham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are rare, related diseases of unknown pathogenesis first described in the 1950s (1-3). GSD, also termed "vanishing bone disease," typically involves a single bone of the axial skeleton and produces cortical resorption and progressive osteolysis of the entire bone with associated proliferation of vascular channels (3,4). GLA is characterized by multifocal angiomatous lesions of the axial and appendicular skeleton confined to the medullary cavity, with frequent involvement of long bones, Division of Neuro-Ophthalmology, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. The authors report no conflicts of interest. Address correspondence to Neil R. Miller, MD, Division of NeuroOphthalmology, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 N Wolfe Street, Baltimore, MD 21287; E-mail: nrmiller@jhmi.edu 70 pelvis, skull, and vertebrae (4-6). Visceral organs, especially the lungs, liver, and spleen, often are involved in both GSD and GLA (4,6-8). Angiomatous proliferation also may extend to adjacent bones and soft tissue (2,4). Most patients present during puberty, although some develop symptoms after the age of 50 years, suggesting a bimodal distribution pattern and/or variation in disease process, such as congenital vs acquired forms. Clinical findings are variable and depend on the affected site. The most common symptom is localized pain; other manifestations include swelling, weakness, and functional impairment of affected limbs (7). Involvement of vertebrae can lead to neurologic symptoms with severe sequelae including paralysis or even death. Visceral involvement can manifest as hepatosplenomegaly, ascites, and chylothorax (9). Although GLA typically is limited to the medullary cavity and does not progress, cortical bone loss in GSD can lead to severe deformity and disability (6), and in the setting of visceral involvement, the disorder can be fatal. Ocular manifestations of GSD are rare. We describe an unusual case of a patient with GSD whose initial manifestation was acute unilateral proptosis. CASE REPORT A 66-year-old woman reported a 3 day history of sudden proptosis. She had a history of hypertension, hyperlipidemia, high-grade ductal breast carcinoma in situ treated with surgical resection, radiation, and maintenance tamoxifen. On examination, visual acuity was 20/20 in the right eye and 20/30 in the left eye. Pupillary testing was normal, there was 5 mm of left proptosis, and ophthalmoscopy was unremarkable. Brain computed tomography (CT) demonstrated intraosseous lesions of the right frontal and left parietal calvaria, and a destructive bony mass involving the left greater wing of the sphenoid with adjacent abnormal appearing orbital soft tissue (Fig. 1). The orbital mass was further characterized with MRI (Fig. 2). Laboratory studies included a normocytic anemia and a normal metabolic panel including a normal level of Stroh et al: J Neuro-Ophthalmol 2018; 38: 70-74 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Axial pre- (A) and postcontrast (B) orbital CT shows osteolysis of the greater wing of the left sphenoid bone with a hyperdense soft-tissue component within the left orbit and extending into the middle cranial fossa. The lesion also extends through the left orbital roof into the anterior cranial fossa (not shown). C. There is a lytic lesion in the right frontal calvarium with areas of rarefaction of the inner and outer tables of the skull. CT, computed tomography. alkaline phosphatase. Other studies included cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), perinuclear antineutrophil cytoplasmic antibody (p-ANCA), erythrocyte site sedimentation rate, C-reactive protein, and immunoglobulin levels including IgG 4 which were all normal or negative. A transcutaneous biopsy of the abnormal orbital soft tissue was performed, but the procedure was complicated by severe bleeding and, therefore, halted. The patient was referred to our institution where she underwent resection of the right frontal skull lesion. Pathology of this lesion was consistent with an interosseous cavernous angioma (Fig. 3A). At the time of our examination, visual acuity was 20/50, right eye and 20/40, left eye, with intact color vision and pupillary reactions. Eye movements on the right were full, whereas on the left there was limited elevation, depression, and abduction. Corneal and facial sensation were intact, and there was 6 mm of left proptosis. Intraocular pressures were 11 mm Hg, right eye and 16 mm Hg, left eye. The anterior segment showed superficial keratopathy on the left, and perimetry demonstrated an inferior visual field defect in the left eye. The fundi were normal. The patient underwent a left frontotemporal craniotomy with transcranial left orbital exploration. The orbital roof and posterior lateral orbital wall appeared thickened and pock- marked and were resected. Although the orbital fat appeared gray, no discreet soft tissue mass could be identified in the orbit and the fat lobules were normal in both size and shape. Nevertheless, multiple biopsy specimens were obtained from the orbit. Pathologic examination of the resected bone revealed changes consistent with an intraosseous angioma (Fig. 3B), and the soft-tissue specimens revealed fat infiltrated by angiomatous tissue (Fig. 3C). Postoperatively, the patient had a marked reduction in proptosis, but 5 months later acuity of the left eye was 7/ 200 with decreased color vision and a left relative afferent pupillary defect. MRI now demonstrated a soft-tissue mass filling the left orbit with evidence of left optic nerve compression. Because of a subsequent back injury experienced during a fall, further imaging was performed that revealed polyostotic disease of the skull, vertebrae, pelvic bones, and ribs (Fig. 4). This was confirmed with a bone scan (Fig. 5), as well as with positron emission tomography. Bone marrow aspiration and biopsy were attempted but were complicated by severe bleeding leading to termination of the procedures. Based on pathologic and neuroimaging findings, our patient was diagnosed with GSD and referred to the Undiagnosed Disease Network at the National Institutes of Health. She is currently undergoing treatment with a bisphosphonate and bevacizumab. This treatment FIG. 2. A. Precontrast axial T1 orbital MRI demonstrates an isointense lesion in the left orbit involving the greater wing of the sphenoid with expansion through the lateral orbital wall. The mass enhances following intravenous contrast (B) and is hyperintense on T2 imaging (C). The lesion also extends through the left orbital roof into the anterior cranial fossa (not shown). Stroh et al: J Neuro-Ophthalmol 2018; 38: 70-74 71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. Biopsy of frontal skull lesion. A. There are vascular spaces with surrounding lamellar and woven bone, consistent with a vascular lesion with focal thrombosis and papillary endothelial hyperplasia (hematoxylin & eosin). Biopsy of left orbital bone (B) and orbital soft tissue (C) demonstrate findings consistent with intraosseous angioma and cavernous angioma, respectively (bar = 100 mm). is not currently approved by the Federal Drug Administration. DISCUSSION GSD is a heterogeneous disorder with a variable natural course. Using the PubMed database, we identified only 1 other case of GSD involving the orbit (10). The patient had involvement of the lateral wall of the right orbit, but no details were given regarding visual function. In addition to its rare ophthalmologic presentation, several features of our case were atypical of GSD. Although the average age of presentation of both GSD and GLA is in the early twenties, our patient presented at age 66 years. GSD has been FIG. 4. Unenhanced coronal (A) and sagittal (B) CT images of the lumbar spine with bone algorithm demonstrate numerous well-defined lytic (black arrow) and sclerotic (white arrow) lesions with preserved bony cortex throughout the vertebral bodies and posterior elements, sacrum, and ilium. CT, computed tomography. 72 Stroh et al: J Neuro-Ophthalmol 2018; 38: 70-74 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 5. Technetium 99m-methyl diphosphonate whole-body scan demonstrates multiple foci of increased radiotracer uptake, including in the left parietal bone, left orbito-zygomatic region, left frontal bone, cervical, thoracic, lumbar spine, bilateral ribs, iliac bones, left acetabulum, and right femoral diaphysis. hypothesized to have a bimodal distribution that may be due to a variation in disease process or epigenetic factors. Studies comparing CT findings in GSD and GLA have demonstrated that cortical loss, progressive osteolysis, or both, associated with clinical manifestations mirroring the sites of involvement are features of GSD, whereas multifocal involvement without clinical symptoms is common in GLA (4,10). Our patient had imaging features of both GSD and GLA. Osteolysis of the sphenoid bone associated with a localized soft-tissue reaction was consistent with GSD, whereas numerous lytic lesions of the axial skeleton confined to the medullary cavity were more typical of GLA (4). Based on the classification of craniofacial lesions described by Kato et al (10), our patient had both Type 1 (multifocal, sparing the cortical boundaries of bone) and Type 2 (diffuse) craniofacial osteolysis, consistent with GSD (Fig. 1). Infiltrative involvement of the soft tissues adjacent to the site of osseous abnormality occurs in GSD, with MRI findings of high T2 signal intensity and intense contrast enhancement (2,4), as was seen in our patient (Fig. 2). However, although Kato et al (10) proposed that lack of an expansive mass is a key feature differentiating GSD from malignancy (10), our patient's imaging demonstrated a destructive mass that exhibited growth over 5 months of follow-up. Our review of the literature using the PubMed database indicates that such rapid progressive soft-tissue involvement in GSD has not been described previously. The pathophysiology of GSD and GLA has yet to be fully elucidated. The disease process may be driven, in part, by both angiogenic and osteoclastogenic cytokine proStroh et al: J Neuro-Ophthalmol 2018; 38: 70-74 duction, including vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), respectively (8,11,12). VEGF and VEGF-C have been implicated in the process of pathologic endothelial cell proliferation, are overexpressed in the serum of GSD patients, and correlate with disease activity and response to interferon-a (IFN-a) therapy in a subset of patients (12,13). Ex vivo cells from a softtissue lesion from a patient with GSD have been shown to secrete high amounts of IL-6, tumor necrosis factor-a (TNF-a), and VEGF-A (11). Hagendoorn et al (8) proposed targeting lymphatic endothelial cell proliferation and outlined potential molecular targets such as VEGF, fibroblastic growth factor, and mechanistic target of rapamycin (mTOR) using VEGF inhibitors, IFN-a, and sirolimus, respectively (8). These antiangiogenic therapeutics might inhibit proliferation of vascular endothelial cells in osteolytic lesions (14). Because of the rarity of GSD and GLA, no evidencebased treatment guidelines exist, and no definitive therapy currently is available (8,15). Potential treatment modalities include medication, surgery, radiation, or a combination thereof (16,17). Reports on the efficacy of a variety of therapies including interferon, bisphosphonates, bevacizumab, calcium, and vitamin D provide only anecdotal evidence, and their therapeutic success is variable. Moreover, because of the variability of natural history, it is difficult to ascertain accurately the effect of medical therapy on clinical course. Bisphosphonates are believed to work by their antiosteoclastic and possibly antiangiogenic properties (15), and their use in GSD and GLA is well established, usually as an adjunct to IFN-a or radiation (7,8). IFN-a2b has been shown to induce and maintain disease stabilization, can be safely combined with bisphosphonates, and has been used as adjuvant therapy after surgical resection (8). The mechanism of IFN's therapeutic benefit in GSD is unknown but is believed to involve downregulation of VEGF expression (18,19). A combination of IFN-a2b and bisphosphonates therefore typically is used as first-line medical therapy (8). Other antiangiogenic agents that have been used to treat GSD and GLA include sirolimus and bevacizumab. Sirolimus, an inhibitor of the mTOR pathway, is hypothesized to exert its antiangiogenic effects by downregulating production of VEGF (18,20) and has been demonstrated to be effective in the treatment of GSD (14,21) as well as complicated vascular anomalies refractory to other therapies (22). There are case reports of patients with GSD treated both successfully (9) and unsuccessfully (12) with bevacizumab. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: I. 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Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57:1018-1024. Stroh et al: J Neuro-Ophthalmol 2018; 38: 70-74 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
Date | 2018-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, December 2018, Volume 38, Issue 1 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s68m1p70 |
Setname | ehsl_novel_jno |
ID | 1404051 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s68m1p70 |