Primary optic nerve and peripheral nerve tumors are common

REVIEW ARTICLe Neural Tumors of the Orbit What Is New? Mark P. Ghassibi, MD, Jan P. Ulloa-Padilla, MD, and Sander R. Dubovy, MD Abstract: Primary neural tumors of the orbit account for approximately 10% of all orbital tumors. Different tumor entities include meningiomas, optic nerve gliomas, neurofibromas, schwannomas, malignant peripheral nerve sheath tumors, and granular cell tumors. This review summarizes current concepts regarding epidemiology, clinical presentation, diagnosis, pathology, immunohistochemistry, prognosis, and treatment for neural tumors of the orbit based on the available literature. Key Words: neural tumors, orbit (Asia-Pac J Ophthalmol 2017;6:273 282) Primary optic nerve and peripheral nerve tumors are common lesions that may arise within the orbit. In a retrospective case series of 1264 patients with orbital tumors, 1 optic nerve/meningeal tumors and peripheral nerve tumors accounted for 8% and 2% of all lesions, respectively. Tumors of the optic nerve include optic nerve sheath meningiomas and benign or malignant optic nerve gliomas. Tumors of the peripheral nerves within the orbit include neurofibromas, malignant peripheral nerve sheath tumors, schwannomas, and granular cell tumors. All of these neural tumors are space-occupying lesions that typically present with gradual vision loss and proptosis. Computed tomography (CT) and magnetic resonance imaging (MRI) are useful adjuncts; however, biopsy is often necessary for immunohistochemical analysis and definitive diagnosis. Prognosis differs between tumor subtype, grade, and clinical symptoms, and treatment options include observation, radiotherapy, chemotherapy, and surgical excision. Meningioma Optic nerve sheath meningiomas are benign tumors that arise from the meningothelial cells of the arachnoid layer within the optic nerve sheath. These tumors comprise 35% of all intrinsic tumors of the optic nerve, 2 with 10% arising within the orbit. 3 They are the second most common optic nerve tumor after optic nerve gliomas. 4 Optic nerve sheath meningiomas comprise 2% of all orbital tumors with a mean age at presentation of 41 to 48 years. 1,3 There is a higher incidence in females (61%) and the majority are unilateral (95%). 3 Meningiomas are more frequent in patients with neurofibromatosis type 2 (NF-2) with an incidence of 9%, 3 often present at a younger age, and may be bilateral. 4,5 Meningiomas From the Florida Lions Ocular Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Received for publication April 12, 2017; accepted May 7, 2017. The authors have no funding or conflicts of interest to declare. Reprints: Sander R. Dubovy, MD, 900 NW 17th St, Room 350, Miami, FL 33136. E mail: sdubovy@med.miami.edu. Copyright 2017 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.22608/APO.2017157 Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 that do not arise from the optic nerve sheath can also present in the orbit. These include intracranial meningiomas originating from the sphenoid wing that secondarily invade the orbit and ectopic meningiomas (10 reported cases in the literature) with no demonstrable connection to the optic nerve or the intracranial meninges. 6 Ectopic orbital meningiomas are thought to arise from congenitally dislocated nests of meningothelial cells, regressed orbital meningoceles located within the orbit, or penetrating trauma that dislocates foci of meningeal tissue into the orbit. 6 The clinical findings of optic nerve meningiomas include visual loss followed by proptosis and chronic optic disc swelling, which can eventually result in optic atrophy. Optic nerve compression may lead to blurriness, reduced color vision, and a relative afferent pupillary defect. 2,3,5 Visual loss is typically gradual, painless, and usually begins 1 to 5 years before presentation. These tumors usually cause an enlargement of the blind spot and/or peripheral constriction of the visual field. 2,3 Proptosis, rarely the initial presenting symptom, is seen in 59% of patients and can range from 2 to 5 mm. 3 On fundus examination, optic nerve edema is typically present when the tumor is located within 1 cm of the globe, and optic disc pallor is seen with chronic posterior compression of the nerve. 7 Optic nerve meningiomas that cause longstanding central retinal vein compression can lead to the formation of optociliary shunt vessels. 8 Although the classic triad of gradual visual loss, optic atrophy, and optociliary shunt vessels is consistent for optic nerve sheath meningioma, it is rare to see all 3 findings in 1 patient and if the triad is seen, it is often relatively late in the course of the disease. 4,5,9 Mao et al 10 reviewed 25 cases of misdiagnosed unilateral optic nerve meningioma and found that they were most frequently classified as acute papillitis (17), followed by optic atrophy (8), ischemic optic neuropathy (5), acute retrobulbar optic neuritis (5), and optic disc vasculitis (3). Ectopic meningiomas within the orbit will present with slow, progressive proptosis. 6 Diagnostic Approaches The diagnosis of optic nerve sheath meningioma may be made with either CT or MRI. 5,11,12 The former demonstrates an enlarged optic nerve with increased peripheral intensity and decreased central intensity, which is described as the tram-track sign. 5 Computed tomography also allows for the visualization of calcifications within the optic nerve sheath, 3,5,8 which indicate slow growth. 13 Magnetic resonance imaging is considered the most sensitive and specific imaging modality for the diagnosis of optic nerve sheath meningioma. 4,11,12 Homogenous enhancement of the lesion with gadolinium is seen on MRI, though the optic nerve itself does not enhance. 4,12,14 T1-weighted MRI with contrast and fat suppression outlines the true anatomic borders of the optic nerve located in the optic canal and orbit and is more useful than CT for the evaluation of intracanalicular, intracranial, and/or www.apjo.org 273

Ghassibi et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 contralateral optic nerve sheath involvement. 4,13 In terms of tumor morphology, one study reported that the most common pattern seen on imaging was tubular, with subgroups of diffuse, apical, and anterior expansion. 13 The diffuse tubular pattern exhibits minimal widening of the optic nerve and more frequent evidence of calcification and tram-tracking. 13 Also, the tubular pattern with apical involvement was found to have worse visual acuity. 13 Another pattern seen was globular, where the tumor extended outside the dural sheath and was associated with worse proptosis. The third most common pattern seen was fusiform. 13 Optic nerve sheath meningiomas can be diagnosed with imaging alone and biopsy is not often required; however, if the patient has atypical sudden or rapidly progressive visual loss, biopsy is warranted. 5 Optic nerve meningiomas arise from the meningothelial cells of the arachnoid villi within the meninges surrounding the optic nerve. 9 These tumors appear grossly as diffuse, plaque-like thickenings of the meninges as they grow circumferentially around the optic nerve or as a globular mass replacing the orbital soft tissue if the tumor extends though the meninges onto the surface of the optic nerve sheath. 3,15,16 Meningiomas may remain localized within the arachnoid, grow to compress the nerve, or invade the dura and extend into the surrounding orbital soft tissues. Histologically, meningiomas display a transitional or syncytial pattern. 5,9 In the transitional pattern, spindle- or oval-shaped meningothelial cells aggregate in whorls with indistinct cell borders (Fig. 1). 9 The tumor cells contain pale nuclei, some of which have inclusion bodies that are cytoplasmic invaginations into the nuclei. Areas of calcification known as psammoma bodies can be present in the degenerated centers of the whorls, and if numerous, may be seen on CT. The syncytial pattern consists of polygonal cells arranged in sheets that are separated by vascular trabecula. 5 Saeed et al 13 reported no correlation between radiologic configuration observed and histologic subtype. Meningiomas typically do not exhibit mitotic figures or areas of necrosis. 3,9,17 Epithelium membrane antigen (EMA) will stain the cytoplasm of neoplastic meningothelial cells (Fig. 1) and helps to distinguish a meningioma from a schwannoma. 9,18 Immunoreactivity of EMA is a characteristic feature of meningiomas, regardless of the pattern of growth. 18 The tumor cells are also positive for vimentin and S-100. 9 S-100 immunostaining is often focal with equal cytoplasmic and nuclear staining, whereas schwannomas exhibit diffuse S-100 staining that is more intense in the nuclei than the cytoplasm. 18 Meningiomas can rarely be positive for cytokeratin. 9,18 Progesterone receptor may also be positive in optic nerve sheath meningiomas (Fig. 1). Thom et al 19 analyzed 30 surgically resected optic nerve sheath meningiomas and found higher levels of progesterone receptor expression compared with benign meningiomas from other intracranial sites. Progesterone receptor expression in meningiomas may be of functional significance in the growth of these neoplasms and is related to the tumor grade and likelihood of recurrence. 19 Aggressive meningiomas may also display a higher percentage of Ki-67 staining, a nuclear antigen present in actively cycling tumor cells (Fig. 1). 20 Optic nerve sheath meningiomas result in a loss of visual acuity that progresses slowly over many years. There is little associated mortality, neurologic morbidity, or metastases. 3,5 The majority of patients will eventually lose vision if the affected eye figure 1. Meningioma. A, Computed tomography showing an isodense mass in the right medial orbit (red arrow). B, Histopathological section [hematoxylin-eosin (H&E) stain, high-power field at 100x magnification] showing a tumor composed of eosinophilic cells. C, Histopathological section (H&E stain, high-power field at 400x magnification) showing bland meningothelial cells in a whorled pattern with indistinct cell borders. D, EMA stain (high-power field at 200x magnification) is positive within the tumor cells. E, Progesterone receptor staining (high-power field at 200x magnification) is positive within the tumor cells. F, Ki-67 proliferation index staining (high-power field at 100x magnification) is approximately 2 3%. 274 www.apjo.org

Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Neural Tumors of the Orbit is not treated. 4,5 In a series of 55 patients, Alper 21 found that optic nerve sheath meningiomas were more aggressive in younger patients. In this study, 5 patients under the age of 35 had intracranial extension and died. 21 If localized to the orbital part of the optic nerve and without significant visual dysfunction, these tumors are tracked with repeated MRI follow-up examinations. Turbin et al 22 examined the visual outcomes in patients with optic nerve sheath meningiomas with similar initial visual acuities that were treated with either observation, surgical therapy, radiation therapy, or a combination of surgical and radiotherapy, and found that the group treated with radiotherapy alone had a significantly better visual acuity outcome than the other groups. 22 External beam radiation is the preferred treatment to preserve vision, 5,22 and Miller et al 8 recommend fractional or stereotactic radiotherapy in cases that present with slow gradual visual loss. This method delivers a sufficient amount of radiation targeted specifically to the meningioma, which minimizes exposure of the surrounding tissues to radiation. 5 In general, surgery is discouraged due to the high likelihood of blindness after tumor resection because of damage to the pial vessels shared by the optic nerve and the meningioma. 5,22 Surgical removal is typically offered after progressive visual loss, to manage disfiguring proptosis, to relieve pain, 5 or in children with more aggressive tumors. 21 Lastly, progesterone receptor expression may be indicative of a potential response of surgically less accessible meningiomas to hormonal treatments. 19 Optic Nerve Glioma Optic nerve gliomas are the most common optic nerve neoplasm and arise from astrocytes within the optic nerve. They comprise approximately 4% of orbital tumors. 1 The majority are benign, occur in children, and are referred to as juvenile pilocytic astrocytomas. 23 However, a malignant form of optic nerve glioma can occur in adulthood and is termed malignant glioblastoma. 24 Ninety percent of optic nerve gliomas are diagnosed during the first 2 decades of life, with a median age of 5 years, and become clinically apparent between 8 months and 38 years of age. 2,23,25,26 These lesions occur more often in females (60%) and are usually unilateral. 8,23 Although the majority of cases are sporadic, it has been reported that 10 70% of patients diagnosed with juvenile pilocytic astrocytoma have associated neurofibromatosis type 1 (NF-1). 8,23,27,28 In patients with NF-1, 8 31% are diagnosed with associated optic nerve glioma. 8,23,27 Bilateral optic nerve gliomas are typically associated with NF-1. 2,29,30 Orbital optic nerve gliomas present with unilateral painless vision loss, proptosis, and optic disc swelling or pallor. 2,8,23 Gradual vision loss is often the initial and most common presenting symptom. 2 Proptosis is often with inferior displacement of the globe. 8 Because these slow growing tumors are typically intraconal, pain and ophthalmoplegia are uncommon and are reported only in very large tumors. 28 The tumor is almost invariably confined by the dura mater and does not invade surrounding orbital structures, although Eghtedari et al 28 reported a case of optic nerve glioma with complete intraocular extension filling the vitreous cavity. If the tumor is near the optic disc, compression can lead to rapid visual loss, optic disc swelling, and a relative afferent pupillary defect. 23 Longstanding compression of the nerve eventually leads to optic atrophy. Central retinal vein compression may lead to central retinal vein occlusion (CRVO), optociliary shunt vessels, rubeosis iridis, and neovascular glaucoma. 2,8,23 It is important to note that not all optic nerve gliomas are symptomatic and they may be found during routine imaging for NF-1. 29 Diagnostic Approaches Optic nerve gliomas appear as iso- or hypoattenuating fusiform enlargements of the optic nerve on CT. 23 Fusiform enlargement without surrounding orbital soft tissue involvement may be seen on MRI, 31 which is the best imaging modality for evaluating intracranial extension including involvement of the optic chiasm. 32 On T1-weighted imaging, gliomas appear hypo- to isointense, and on T2-weighted imaging they appear mildly to strongly hyperintense. 8,23,32 The optic nerve itself cannot be distinguished from tumor, a characteristic that helps differentiate a glioma from a meningioma. 32 In patients with NF-1, the nerve typically demonstrates diffuse enlargement, kinking, and buckling; whereas in patients without NF-1, the nerve shows fusiform enlargement with clear margins due to the intact dura. 32,33 Intracranial extension of the tumor is more often seen in patients without NF-1. 23,29 All children with NF-1 younger than age 8 should have thorough ophthalmological examinations annually and then every 2 years until age 18; however, serial neuroimaging is not indicated if the patient is asymptomatic. 23,30 In patients without NF-1, the optic nerve parenchyma is grossly expanded resulting in a fusiform appearance and an intact, thinned surrounding dura. In those with NF-1, the tumor can break through the pia-arachnoid and fill the subdural space. 8 Histologically, optic nerve gliomas consist of spindle-shaped astrocytes with elongated, hair-like, or pilocytic processes. 9,32 The astrocytes are cohesive with oval nuclei and are rarely hyperchromatic (Fig. 2). Mitotic figures are typically absent. The pilocytic cells form interlacing bundles that irregularly distend the pial septa of the optic nerve and some tumors may show thickened vessel walls and microcystic spaces filled with acid mucopolysaccharide. 9 Rosenthal fibers, which represent degenerative changes of the astrocytes and are composed of aggregates of glial filaments, 9,32 appear as eosinophilic cylindric swellings (Fig. 2). Although the appearance of optic nerve gliomas in patients with and without NF-1 is the same, these tumors tend to be more aggressive in patients without NF-1. 29 Some pilocytic astrocytomas may cause a reactive arachnoid hyperplasia 9,32 that can be mistaken for a meningioma on pathology if the glioma is not seen within the biopsied tissue. In contrast to meningiomas, however, reactive arachnoid hyperplasia consists of discontinuous nests of proliferating meningothelial cells and does not invade into the adjacent dura. 32,34 DNA analysis can also be helpful in distinguishing the 2, as reactive arachnoid hyperplasia lacks NF2 and 4.1B gene deletions coding for the merlin and 4.1B proteins, typically found in meningiomas. 34 Optic nerve gliomas stain positively for glial fibrillary acidic protein (GFAP) and negatively for S-100 and EMA. 9 Reactive arachnoid hyperplasia can be distinguished from an optic nerve sheath meningioma with immunohistochemistry showing an absence of the merlin and 4.1B proteins. 34 www.apjo.org 275

Ghassibi et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 dysfunction. 24,40 Because these tumors present with acute visual loss, they can be mistaken for optic neuritis or anterior ischemic optic neuropathy. 41,42 Death usually occurs within 1 year. 8,24,40,41 figure 2. Pilocytic astrocytoma. A, Histopathological section (H&E stain at 200x magnification) showing pilocytic astrocytes and eosinophilic cellular processes (Rosenthal fiber, red arrow). B, Positive GFAP immunohistochemical staining at 100x magnification. Optic nerve gliomas are almost always benign, grow very slowly, and can exhibit spontaneous regression. 2,8,29,35 There is excellent long-term survival regardless of treatment even in rare cases of tumor progression or recurrence. 29 Patients are typically followed at regular intervals with neuroimaging and clinical examination, and no intervention is taken until vision begins to deteriorate. 8,23 Miller et al 8 recommend that intervention should only be considered in cases with unacceptable proptosis, progressive deterioration of vision, or definite tumor growth and/or extension seen on MRI. Treatment modalities include chemotherapy, 36 radiotherapy, 2,37 and surgical excision. 2,8 When indicated, complete removal of the tumor is associated with excellent long-term prognosis. However, the value of chemotherapy or radiotherapy is less clear. 38 Tow et al, 29 in a retrospective study of 47 patients with anterior visual pathway gliomas, reported that radiation therapy at doses between 4500 and 5600 cgy can halt tumor progression over an extended period of time. They also stated that it was not clear whether chemotherapy was effective in halting tumor progression. 29 Listernick et al 39 reported that carboplatin chemotherapy resulted in decreased tumor size and visual improvement. Malignant Optic Nerve Glioma Malignant optic nerve gliomas are rare, high-grade tumors that present as a World Health Organization (WHO) grade III anaplastic astrocytoma or WHO grade IV glioblastoma. 24 They have a rapid course resulting in progressive visual loss, neurological deficits, and eventual death. 8,24 These tumors occur in adults with a mean age of onset of 57 years 8,24,40,41 and occur equally in males and females. 8,23,41 The typical pattern of presentation for malignant optic gliomas that arise in the proximal part of the optic nerve is unilateral blurring of vision, optic disc swelling, and posterior pole hemorrhage. 23,40 The fundus often resembles ischemic CRVO and neovascular glaucoma can develop. 8 Tumors in the distal part of the optic nerve are associated with pale, normal-appearing optic discs. 42 After 5 6 weeks, the contralateral eye becomes affected as the tumor spreads, which eventually leads to complete blindness. 2,8,41 In the latter stages of disease, tumor invasion can lead to neurologic deficits such as hemiparesis and hypothalamic 276 www.apjo.org Diagnosis An initial diagnosis of optic neuritis is frequently made because of the acute vision loss, papilledema, retrobulbar pain, and brief visual improvement with intravenous corticosteroids. 41,42 Neuroradiologic findings for these tumors are nonspecific and include contrast enhancement and thickening of the optic nerve on T1-weighted MRI. 8,24,41 Enlargement of the optic nerve due to malignant glioma cannot be distinguished from enlargement due to other causes. 40,41 Typically, CT imaging is not helpful. 40 For diagnosis, lateral orbitotomy is typically performed to biopsy the tumor. 24 Malignant optic nerve gliomas are either WHO grade III anaplastic astrocytomas or WHO grade IV glioblastomas. High-grade astrocytomas are defined by increased mitotic activity and a grade IV diagnosis requires the presence of necrosis or vascular proliferation. Traber et al 24 reported a case of glioblastoma of the optic nerve sheath and chiasm that displayed pseudopalisading necrosis and microvascular proliferation on histology. On gross pathology, malignant optic nerve gliomas are vascular, variably necrotic, and occupy the majority of the optic nerve. The tumor tends to infiltrate the meninges and the surrounding soft tissue. 8 Histology shows cellular pleomorphism, hyperchromatic nuclei, mitotic activity, and areas of necrosis and hemorrhage, which are all absent in a benign pilocytic astrocytoma. 24,32,41 Although these tumors are very aggressive, intraocular tumor extension is very rare. 24 The advised treatment for malignant optic nerve gliomas consists of surgery or biopsy to the extent feasible followed by radiotherapy alone for WHO grade III tumors and temozolomide chemoradiotherapy for WHO grade IV tumors. 24,43 In patients that do not undergo treatment, mean survival is typically less than 1 year. The addition of temozolomide to radiotherapy increased the median survival of glioblastoma patients by 2 3 months and the likelihood of 2-year survival from 10% to 26%. 43 However, no therapy has proven to stop the tumor, 23 which results in death within 1 to 2 years. 24,40 42 Peripheral Nerve Sheath Tumors Peripheral nerve sheath tumors (PNSTs) may involve cranial nerves 3 7 within the orbit and are derived from neuroectoderm and neural crest. 44 46 They comprise approximately 2 4% of orbital tumors. 1,2,46 The most common PNSTs include neurofibromas and schwannomas (neurilemomas). 46 Malignant peripheral nerve sheath tumors (MPNSTs) are relatively rare. 45 Neurofibromas can be further classified into solitary, diffuse, and plexiform neurofibromas. 9 Most benign PNSTs affect adults between ages 20 and 60 years except for plexiform neurofibromas, with half diagnosed between ages 1 and 5 years. 44,46 There is no sex or racial predilection. 44 Although neurofibromas are associated with NF-1, 90% of solitary orbital PNSTs are not associated. 44 Typically, benign PNSTs are slow growing, noninvasive tumors and their presentation is largely dependent on location within the

Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Neural Tumors of the Orbit orbit. 46 Another benign neural tumor derived from peripheral nerve tissue that can arise in the orbit is a granular cell tumor (GCT). Neurofibroma Neurofibromas are benign, slow-growing PNSTs composed of Schwann cells, fibroblasts, and fibrous connective tissue 9 that can present in the orbit as 3 different types: plexiform neurofibroma, diffuse neurofibroma, or solitary neurofibroma. 9,44 Rarely, postamputation neuromas within the orbit can occur after blunt or surgical trauma. 47,48 Plexiform neurofibromas are the most common type within the orbit 1 and involve multiple adjacent nerve branches. The result is a composite network, or plexus, of infiltrative, poorly circumscribed, and thickened nerve bundles. 46 Plexiform neurofibromas have been described as pathognomonic for NF-1 and usually appear in the first decade of life, with 50% diagnosed between ages 1 and 5. 44,46 One study reported 2 patients with plexiform neurofibromas that did not meet the diagnostic criteria for NF-1 and did not have the NF-1 mutation on DNA analysis. 49 NF-1 patients have a 5% chance of developing a plexiform neurofibroma. 50 The molecular mechanism is attributed to biallelic loss of the tumor suppressor gene NF-1 in Schwann cells. 44 Of note, patients with NF-1 also have 10 15%, 2 8%, and 1.5% chances of developing an optic nerve glioma, optic nerve sheath meningioma, or orbital schwannoma, respectively. 44 Isolated or localized neurofibromas are nonencapsulated, well-circumscribed lesions that present in the third to fifth decades and are usually sporadic. 51,52 In patients with isolated neurofibromas, 10 28% have associated NF-1, 32,53,54 and in those with NF-1, there is a 2 18% chance of developing a solitary or diffuse neurofibroma within the orbit. 50 Isolated neurofibromas are the least vascular of the 3 types. The diffuse type is similar to the plexiform neurofibroma in that it is infiltrative and presents earlier in life; however, these tumors infiltrate into the subcutaneous fat and lead to characteristic thickening of the subcutaneous and dermal tissues. 9 They also tend to be more vascular. 44 Diffuse neurofibromas were found to be associated with NF-1 in at least 10% of cases. 55 Lastly, traumatic or amputation neuromas can form after damage to a peripheral nerve within the orbit. 9 They are the result of a reactive process to injury at sites of previous surgical intervention or trauma. 48 One study reported 2 cases of traumatic neuromas in the orbit that presented 17 and 25 years after enucleation. 47 Clinical Presentation Plexiform neurofibromas of the orbit typically present in childhood with an S-shaped upper eyelid deformity with a bag of worms consistency upon palpation and associated lid swelling. 9,32,44 These infiltrative, multinodular masses grow along the course of peripheral nerves. 50 Isolated neurofibromas present in middle age as a mass typically in the superior orbit where there is a greater number of sensory nerves. In approximately 50% of cases, the slow progressive enlargement of the tumor leads to unilateral proptosis and lid swelling of less than 1-year duration. 44 In 4 20% of cases, the presenting features are ptosis, decreased vision, and diplopia. 46,56 Pain and visual obscuration may signal nerve root compression, globe indentation, or rarely malignant transformation. 46 Typically, an isolated neurofibroma will not affect visual acuity unless the optic nerve is compressed. Diffuse neurofibromas often present in the head and neck region of children and young adults with a characteristic plaquelike thickening of the dermal and subcutaneous tissues due to tumor infiltration into the subcutaneous fat. Kapadia et al 57 reported a case of an 8-year-old female who presented with a progressively enlarging orbital mass and eyelid swelling. The tumor was present throughout the orbital fat, much of the extraorbital muscle, and surrounded the optic nerve and globe. Messmer et al 47 reported 2 cases of slowly enlarging masses in orbital sockets 17 and 25 years after enucleation, which were diagnosed as amputation or traumatic neuromas. The patients both presented with proptosis and increasing discomfort in the orbital socket. Associated pain is rarely encountered but may be the result of mechanical irritation of the amputation neuroma or by retracting scar tissue. 47 Diagnosis Clinical examination alone is insufficient to differentiate neurofibromas from other slow-growing orbital tumors. Both CT and MRI provide useful information about tumor structure and location, which can narrow down the differential diagnosis. 44 Neurofibromas are generally extraconal because they frequently arise from sensory branches of the trigeminal nerve. 32 In addition, they often do not have calcifications like schwannomas or meningiomas. On CT, plexiform neurofibromas will appear as multilobular, oblong, diffuse masses and exhibit a greater degree of infiltration of adnexal structures compared with isolated neurofibromas (Fig. 3). 58 In addition, CT may show the absence of one or both sphenoid wings, which is characteristic of NF-1. 44 On MRI, plexiform neurofibromas appear as serpentine soft-tissue figure 3. Plexiform neurofibroma. A, T2-weighted MRI showing a well-circumscribed enhancing lesion in the right medial anterior orbit (red arrow). B, Histopathological section (H&E stain, high-power field at 100x magnification) showing tumor cells in variably encapsulated areas in a plexiform configuration. C, S-100 stain at 200x magnification highlighting the tumor cells. www.apjo.org 277

Ghassibi et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 masses with heterogeneous uptake of contrast material. 32 They are heterogeneous in intensity on T1-weighted imaging and hyperintense on T2-weighted imaging. 32 On CT, isolated neurofibromas demonstrate homogenous intensity and may be smoothly marginated, round, ovoid, or lobulated. 3,44 Diffuse neurofibromas are poorly defined and irregular with variable enhancement on CT. 44 On MRI, neurofibromas are hyperintense to orbital fat and isointense to the extraocular muscles and brain on T1-weighted imaging. 3 On T2-weighted imaging, they are hyperintense to orbital fat and can display a peripheral ring of hyperintensity creating a target sign. 58 Clinical and imaging features of isolated neurofibromas may be indistinguishable from schwannomas. 32 Plexiform neurofibromas grossly appear nodular and tortuous, are not encapsulated, and grow in a crab grass fashion involving orbital tissues. 9 Isolated neurofibromas are well-circumscribed lesions and can have a pseudocapsule consisting of a cellular perineural sheath. 54 Diffuse neurofibromas are more vascular and infiltrate into surrounding subcutaneous fat while also entrapping structures of the ocular adnexa. 44 Histologically, neurofibromas are composed of wavy bundles of Schwann cells and endoneural/perineural fibroblasts within a stroma rich in hyaluronic acid and variable amounts of collagen (Fig. 3). 9 Bodian stain can highlight myelination. 9 In cases of traumatic neuroma, 47 the pathology has been described as cystic masses containing irregular tangles and whorls of proliferated axons, Schwann cells, and connective tissue. Schwann cells stain positively for the S-100 protein (Fig. 3) and the perineural cells may stain positively for EMA. 9,59 commonly located in the superior quadrant, inferior displacement with proptosis is seen. 63,65 Diagnosis Schwannomas are well-circumscribed, slowly growing lesions that mold to the shape of the cavity and have smooth borders. 66 A CT scan displays a homogenously dense, nonenhancing mass that may contain calcifications. These lesions are usually extraconal (Fig. 4), whereas meningiomas are typically intraconal, and may extend into the superior orbital fissure. 32,66 Shen et al 67 reported that on MRI, the Antoni A regions displayed intermediate signal intensity with post contrast enhancement in T1- and T2-weighted imaging, whereas the Antoni B regions displayed hypointensity in T1- and hyperintensity in T2- weighted imaging. T1-weighted MRI with fat suppression will display a cystic mass representing mucinous degeneration. 68,69 Schwannomas can be difficult to differentiate from isolated neurofibromas on imaging. These tumors are well-circumscribed, encapsulated, and well-vascularized. Histologically, they are composed of 2 morphologic areas: Antoni A areas displaying spindle-shaped cells with nuclear palisading forming solid cellular areas and Antoni B areas displaying loose, stellate cells suspended in a mucinous matrix. 9 Nuclear palisading and highly oriented, polar cytoplasmic processes are referred to as Verocay bodies (Fig. 4). A case of orbital melanotic schwannoma was reported in the literature. 70 These tumors stain positively for S-100 protein. One case Malignant transformation of neurofibromas is rare. 60 Plexiform neurofibromas are highly infiltrative and vascular, and complete excision can be difficult. 1,56 In children at risk for amblyopia, debulking procedures can be performed to reduce tumor size. 44 Benign isolated neurofibromas should be excised in toto without breaking the capsule. 44 Schwannoma Schwannomas are benign peripheral nerve sheath tumors primarily composed of Schwann cells, which produce the myelin sheath around peripheral axons. They are the most common PNST arising within the orbit. 1 It is believed these tumors can arise from the sympathetic nerves that are tightly adherent to the optic nerve sheath, 61 the supraorbital or infraorbital nerves, 62 or typically from the first division of the trigeminal nerve. 63 Most often, this tumor is sporadic but they may occur in association with NF-1 or NF-2. It has been reported in both children and adults. Although typically unilateral, 1 case has been reported with bilateral orbital schwannomas. 64 Orbital schwannomas present with gradual proptosis and lid swelling. Later manifestations include diplopia, ocular motility restriction, mild worsening of visual acuity, and optic nerve compression leading to scotomas. 3,44,63 Because they are most 278 www.apjo.org figure 4. Schwannoma. A, MRI axial view showing a wellcircumscribed, enhancing mass (red arrow) that is isointense to muscle on T1-weighted imaging. B, MRI coronal view showing the mass in the left lower quadrant (red arrow). C, Histopathological section (H&E stain, high-power field at 100x magnification) showing dense (Antoni A, asterisk) and loose hypocellular (Antoni B) areas characteristic of schwannoma. D, H&E stain at 200x magnification showing spindleshaped cells with foci of Verocay bodies located within the dense areas. E, S-100 stain at 200x magnification is positive within the tumor cells.

Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Neural Tumors of the Orbit reported progesterone receptor immunohistochemical staining within the tumor. 71 Schwannomas are surgically excised in toto and recur if not completely excised. 72 Malignant transformation has been reported, 73 and clinicians should be suspicious with an increase in growth rate or development of pain. Malignant Peripheral Nerve Sheath Tumor Malignant PNSTs arise from Schwann cells, perineural cells, and endoneural or epineural fibroblasts. 74 These tumors can may originate from preexisting neurofibromas or schwannomas. 75 Around 2% to 29% of patients with this tumor have a history of NF-1. 74 The age of presentation varies from 4 days to 75 years. 60,75,76 The clinical history is usually that of rapid tumor growth causing pain, redness, hyperesthesia in the distribution of the nerves involved, and rapidly progressing proptosis. 3,44,60,74 Most MPNSTs develop in the superomedial orbit from the supraorbital branch of the trigeminal nerve. These tumors are cystic on palpation. 60 Malignant PNSTs can appear encapsulated and circumscribed. On histology, dense fascicles of spindle cells alternate with less cellular areas. These tumors are also biphasic with a spindle-cell component and an epithelioid component. The spindle cells demonstrate abundant eosinophilic cytoplasm and large pleomorphic nuclei with prominent nucleoli. Areas of necrosis can be seen with surrounding palisading spindle cells (Fig. 5). 9 The tumor cells stain positively for S-100 in 50 90% of cases. SOX10 has also been reported as a useful marker. 77 Malignant PNSTs can spread along peripheral nerves into the cranium, which can lead to neurological symptoms in addition to orbital complaints. 44 Radical surgery, including exenteration, is often the best management. If there is incomplete excision, the tumor can recur within months 9 and can extend intracranially or metastasize to regional lymph nodes, the mediastinum, and the lungs. More than 50% of reported patients died between 1 and 5 years after surgery. 66,76 Granular Cell Tumor Granular cells tumors arise from the peripheral nerve sheath and are usually benign. It is widely believed that they arise from Schwann cells due to their frequent association with peripheral nerves and electron microscopic findings of a basal lamina around cells and cytoplasmic inclusions resembling degenerated myelin. 78,79 They are typically seen in the soft tissues of the orbit, specifically involving the extraocular muscles. 9 The inferior and medial rectus muscles are most commonly affected and it has been hypothesized that they often occur in the extraocular muscles because of their dense neural supply. 78 Although granular cell tumors are regarded as benign, they can exhibit local infiltration of surrounding tissues. 79 Granular cell tumors typically present as slow-growing, solitary, painless lesions that result in worsening proptosis. Because of frequent extraocular muscle location, diplopia is a commonly reported symptom. 78 This tumor usually presents in the third to sixth decade of life and is unilateral. Women are more often affected. 79 Diagnosis On CT, these tumors appear as enhancing isodense or hyperdense round lesions that are well-defined. On T1-weighted MRI, they are isointense relative to the extraocular muscles and figure 5. Malignant peripheral nerve sheath tumor. A, MRI coronal view showing a hypointense, enhancing mass (red arrow) on T1 imaging that involves the inferior rectus muscle. B, Gross section showing a tan, white mass (asterisk) inferior to the globe. C, Histopathological section (H&E stain at 40x magnification) showing tumor (asterisk) present inferiorly that extends into skeletal muscle. D, Histopathological section (H&E stain at 100x magnification) showing a tumor with nodular and fascicular growth patterns. E, H&E stain at 400x magnification showing the mitotically active somewhat cytologically uniform appearing malignant spindle-cell neoplasm. www.apjo.org 279

Ghassibi et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 important for the characterization of these tumors; however, immunohistochemistry is a useful adjunct for making the diagnosis. Meningiomas are positive for EMA and S-100, whereas gliomas are positive for GFAP and negative for S-100 and EMA. Peripheral nerve sheath tumors contain Schwann cells that stain positively for S-100. Perineural cells may also be positive for EMA. Granular cell tumors stain positively for S-100 and may be positive for CD68 and leu-7. figure 6. Granular cell tumor. A, MRI axial view showing a hypointense, enhancing mass (red arrow) on T1 imaging that involves the medial rectus muscle. B, MRI coronal view showing the same mass (red arrow). C, Histopathological section (H&E stain, high-power field at 400x magnification) showing eosinophilic tumor cells with granular cytoplasm and bland nuclei. D, S-100 stain at 400x magnification highlighting the tumor cells. E, Neuron specific enolase (NSE) at 400x magnification highlighting the tumor cells. on T2-weighted imaging, they are hypointense relative to fat (Fig. 6). 78 The tumors are nonencapsulated and have invasive borders. Histologically they display lobules and cords of polyhedral and spindle cells with eosinophilic, granular cytoplasm (Fig. 6). 9 The cytoplasmic inclusions are PAS-positive, diastase resistant, and contain lipid. Mitotic figures and necrosis are not characteristically seen. 79 The cells of this tumor stain positively for S-100 59,78 and can be positive for CD68 59 and leu-7. 79 They are negative for myoglobin and neuron-specific enolase. 79 Treatment Complete surgical removal is the treatment of choice. 78 However, when diplopia was present, complete excision of the granular cell tumor did not improve eye motility in 73% of cases according to a large review. 78 Dunnington 80 reported a case of a malignant orbital granular cell tumor that recurred after excision and metastasized. Summary and Conclusions Primary neural tumors of the orbit arise from the optic nerve or from peripheral nerves within the orbit. Tumors of the optic nerve include meningiomas, pilocytic astrocytomas, and malignant optic nerve gliomas. Peripheral nerve sheath tumors include neurofibromas, schwannomas, malignant peripheral nerve sheath tumors, and granular cell tumors. 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