Optic nerve sheath meningioma (ONSM) is the most common primary tumor arising from the optic nerve sheath. It constitutes 2–5% of all primary orbital tumors and 2% of all meningiomas [2, 21]. ONSM is usually a disease of adulthood, and patients younger than 20 years account for only 4% of all primary ONSM [42]. The vast majority of primary pediatric cases arise from the intraorbital nerve sheath, with only 8% deriving from the intracanalicular region [42]. A female predominance is noted in both adult and pediatric ONSM [43].

Exposure to radiation is one of the most consistent risk factors associated with developing meningioma [21, 44]. Meningiomas frequently express hormone receptors (estrogen, progesterone, and/or androgen) and have been reported to change in size during pregnancy and menopause, leading many researchers to consider the relationship between endogenous and exogenous hormones and meningioma risk. However, studies examining exogenous (e.g., use of oral contraceptives or hormone replacement therapy) or endogenous (e.g., parity, age at menarche, menopausal status) hormones have not demonstrated a consistent risk of meningioma [44].

The classic triad of optic atrophy, visual loss, and opticociliary shunt vessels is pathognomonic for ONSM but occurs as a triad in a minority of patients [42, 45]. The more common presentation includes painless, progressive visual acuity loss or visual field deficit over 1–5 years [45, 46]. In a review of primary pediatric ONSM, the most common clinical features included visual acuity loss (80%), visual field defects (48%), mild to moderate proptosis that was generally <5 mm (68%), optic disc atrophy (63%), optic disc edema (38%), and optociliary shunt vessels (28%) [43].

In children, ONSM is often associated with NF2. In a review of the literature, 5–7% of patients with NF2 also had ONSM, although these were not population-based studies and selection bias was unavoidable [47]. However, up to 10% of children with isolated meningioma eventually develop clinical stigmata of NF2 [48], and ONSM in a child should prompt evaluation for other stigmata of NF2.

On CT imaging, ONSM may demonstrate areas of calcification. Although CT is useful for assessing configuration, bony changes, and calcification [1], MRI is superior for the assessment of soft-tissue involvement in the orbit and the evaluation of intracranial extension [43]. Fat-suppressed MR imaging with gadolinium contrast is the modality of choice for the evaluation of these tumors (Fig. 15.2). ONSMs are generally iso- or hypointense on T1-weighted images and hyperintense on T2-weighted images [49]. They are homogeneously enhancing masses that surround the optic nerve, which may be central or eccentrically positioned [1]. Meningiomas may cause an expansile mass or a thin sheet around the optic nerve, termed “en plaque meningioma” [1], which produces a “tram track” sign (when imaging along the length of the optic nerve) or “target sign” (on coronal imaging) [50]. Because of their hypercellular nature, meningiomas often show restricted diffusion with low apparent diffusion coefficient (ADC) values on diffusion-weighted imaging [51, 52].

Two histologic patterns of meningioma are most common: a meningothelial pattern is characterized by sheets of polygon-shaped cells with interspersed vasculature trabeculae, and a transitional pattern demonstrates whorls of concentric spindle cells with occasional psammoma bodies [45, 46]. Among limited specimens in children, transitional and meningothelial were the most common histologic subtypes [43]. Meningiomas are graded as well-differentiated (WHO grade I), atypical (WHO grade II), or malignant (WHO grade III). In patients of all ages, WHO grade I histology is the most common in ONSM.

Similar to ONGs, treatment for ONSM is commonly intended to preserve vision and is rarely required to preserve life. Pediatric ONSM is often considered more aggressive than its adult counterpart and is associated with higher rates of intracranial extension and recurrence [42, 45, 46, 53]. However, tumor-related mortality is no higher among children than adults, and in small cohorts, there has been no increased risk to vision in the contralateral eye among younger patients. There have been no reported deaths due to primary ONSM in children [43].

Vision loss in ONSM is thought to be caused by vascular compromise due to mass effect on the pia mater inducing ischemic changes that interfere with axonal transport [54]. Surgical resection is often impossible without significant risk of blindness in the affected eye [45, 46]. Fortunately, surgical biopsy is largely unnecessary, given the typical imaging features, examination findings, and clinical presentation of ONSM, although some have recommended biopsy in pediatric cases due to their relative rarity [43, 54]. Likewise, surgical fenestration of the dural sheath is rarely used because any observed improvements are frequently temporary due to continued tumor progression [54]. Surgical resection is therefore reserved for those patients who have already experienced significant compromise to their vision, those with disfiguring proptosis, or those with intracranial extension at risk for contralateral involvement [42].

Stereotactic fractionated radiotherapy is the therapy of choice for most adult patients and results in preservation or improvement in vision in approximately 80% of patients [54]. In a review of 64 subjects treated for ONSM and followed for at least 50 months, radiation alone preserved visual acuity, while other treatment modalities were associated with decreased visual acuity [55]. However, it is important to note that late complications of radiation can be substantial. Orbital radiation has been associated with local dermatologic changes, radiation retinopathy, central retinal artery occlusions, encephalopathy, and premature atherosclerosis, as well as secondary meningiomas [43]. Although conformal radiation is used routinely in adults, few cases in children have been documented, and the potential benefits of radiation in terms of stabilization of vision must be balanced against the risk of radiation-induced toxicities measured over the remaining life span of the patient.

Suspected pediatric primary ONSM should prompt investigation of concurrent NF2, and radiation should be avoided in individuals with NF2 whenever possible due to the increased risk of secondary malignant neoplasm or malignant transformation [56, 57]. If the ONSM is sporadic, vision is severely compromised and the tumor is limited to the orbit, then surgical resection can be curative. If vision is threatened but usable vision can be maintained, the risks and benefits of radiation therapy should be weighed for each case individually [43].

Children with NF2 treated with ionizing radiation have approximately 10 times the risk of developing a secondary neoplasm compared to children with NF2 treated conservatively [57]. However, there have been few studies to date investigating the late effects of radiation therapy in children with NF2-related ONSMs. Patients with NF2 are at increased risk for secondary tumors due to a defect in the NF2 tumor suppressor gene, and radiotherapy may present an increased burden to this population [47]. While visual loss will generally occur in untreated ONSM, it often is slow, is limited to the affected eye, and is not associated with mortality [58]. Further research in the late effects of treatment in children with NF2 is needed to help inform the clinical management of these tumors.

Plexiform neurofibromas (PN) are common benign tumors of peripheral nerves associated with NF1. These tumors often arise in the first decade of life and can involve any peripheral nerve although sensory nerve involvement of the orbit and periorbital region is common [21]. Plexiform neurofibromas that infiltrate the orbit, temporal region, and/or eyelids are called orbitotemporal plexiform neurofibromas (OPPN) and can cause significant disfigurement and interfere with vision [59]. Most of these tumors present within the first 2 years of life [59, 60]. Incidence of NF1-associated PN throughout the body ranges from 20% to more than 50% [61, 62]. The incidence of OPPN in NF1 is unknown but likely less than 10%.

Most PN are believed to be congenital and grow rapidly during early childhood [60], whereas PN found in adults may be more stable [63, 64]. Plexiform neurofibromas have an approximately 10% lifetime risk of transformation to malignant peripheral nerve sheath tumors over a lifetime, but the risk of malignant transformation specifically in OPPN is unknown.

Most OPPN occur in the setting of NF1. Although OPPN are less common than ONG in children with NF1, their effects can be equally devastating to vision. Infiltration behind the orbit can cause proptosis, compression of the eye affecting globe length with resultant refractive error, as well as expansion of the eyelids and periorbital structures causing ptosis and obstruction of vision. These unilateral changes affecting the globe and visual axis put children at risk for amblyopia [59]. Etiologies of amblyopia can also include strabismus, occlusion, anisometropia, as well as the other etiologies described above.

OPPN often presents as a nodular periorbital mass, eventually progressing to mechanical blepharoptosis and eventually amblyopia. OPPN may extend into neighboring structures (forehead, midface) to cause further disfigurement and can invade the cavernous sinus. OPPN may also be associated with sphenoid wing dysplasia, thus allowing communication between the middle cranial fossa and the orbit with potential compression of the extraocular muscle and the optic nerve by the anterior temporal lobe [65].

MR is frequently used to evaluate OPPN and assess its extension into soft tissues of the periorbital region. OPPN commonly appear as a nodular mass that infiltrates soft tissues (Fig. 15.3). The tumor is most often isointense on T1-weighted images and typically hyperintense on T2-weighted images. Areas of central low signal can frequently be seen on T2-weighted images. Tumors demonstrate variable contrast enhancement [1, 21]. OPPN may be difficult to distinguish from schwannomas, but OPPN are generally more infiltrative [1]. In addition, when there is clinical suspicion, PET imaging can help to detect sarcomatous transformation of PN [66, 67].

Neurofibromas are benign nerve sheath tumors that form circumscribed tan-white masses when examined grossly. PN form large multinodular masses that are defined by their involvement of numerous nerve fascicles or multiple components of a nerve plexus. Microscopically, PN often show an admixture of areas resembling localized and diffuse-type neurofibromas [68]. Degenerative atypia, in the absence of hypercellularity, has been interpreted by some pathologists as “atypical neurofibroma,” and there are concerns that such findings are a precursor for malignant transformation.

Although guidelines for surveillance are not well established, children with OPPN should undergo comprehensive ophthalmologic evaluation regularly to test visual acuity, evaluate motility, and assess intraocular pressure and cycloplegic refraction [59]. Ophthalmologic examinations should occur biannually while children are young and at increased risk of continued tumor growth [59, 64].

Newly diagnosed OPPN should be observed, as many of these tumors will not progress. Unfortunately, there are no proven medical therapies to shrink or stop OPPN growth. Although some have attempted early surgical treatment to avoid further deformity and preserve vision [65, 69], surgical resection is typically not curative and usually consists of debulking procedures with reconstruction and ptosis repair [60].

The success of surgical resection is limited by the high risk of recurrence in subtotally resected tumors, particularly in young children [59, 70]. Debulking may be considered for visual decline, progressive disfigurement, or tumor progression toward a critical structure, but disease recurrence with functional and aesthetic relapse should be expected [63, 71]. In one sense, the term recurrence is really a misnomer as complete tumor resection is rare, and thus residual tumor can still continue to grow. Associated ophthalmic complications of OPPN, such as strabismus, amblyopia, and ptosis, should be treated nonsurgically whenever possible, but concerns for amblyopia as well as disfigurement may become important considerations for surgical intervention. Because recurrence is so common and OPPN management is multidisciplinary, children with OPPN should be referred to a specialist with experience in PN and supported by a multidisciplinary NF clinic.

Despite the impact that these tumors can have on vision and physical deformity in children with NF1, few guidelines exist regarding best clinical practices. Children with OPPN require coordinated, multidisciplinary care from ophthalmologists, surgeons, and oncologists well versed in NF1. The rise of new medications targeted at the molecular abnormalities within the tumor raises the possibility of effective therapies in the future [72]. In fact, a recent phase I study of the MEK inhibitor selumetinib has resulted in partial responses in over half of PN treated [73].

Consensus documents, similar to those available for ONG [8], are a necessary first step to directing clinical care and guiding future research for this tumor. A multidisciplinary task force, the OPPN Working Group, met in 2013 to discuss recommendations for care and challenges in clinical trial design for these complex tumors. Consensus recommendations from this group have been submitted for publication [74].

Rhabdomyosarcoma is the most common primary orbital malignancy in children [2, 4, 75] and accounts for 5% of all childhood cancers [76]. This tumor occurs in the orbit in approximately 10% of all pediatric cases. Tumors in the orbit, conjunctiva, or eyelid are together called orbital rhabdomyosarcoma and have a more favorable prognosis than in many other locations [4]. However, tumors that invade the nasal cavity, paranasal sinuses, or nasopharynx are considered to be parameningeal, require more intensive therapy, and have a worse prognosis.

Approximately 350 new cases of rhabdomyosarcoma occur in the United States each year, of which roughly 35 are orbital. Rhabdomyosarcoma has a bimodal age distribution: although most tumors are diagnosed between 2–5 years of age, a second peak is seen in adolescence [77]. The mean age at diagnosis for orbital rhabdomyosarcoma is 8 years of age, and males are more frequently affected than females [75, 78].

Although orbital rhabdomyosarcoma can rarely present insidiously, the most common presentation is rapid onset and progression of proptosis and displacement of the globe [75]. Among 33 consecutive cases of orbital rhabdomyosarcoma, the most common findings included proptosis (79%), paraxial globe displacement (79%), conjunctival congestion (61%), blepharoptosis (55%), dilated episcleral vessels (42%), and ocular motility restriction (42%) [78]. Changes in adjacent bone are frequently seen, and evaluation of intracranial extension and invasion of the paranasal sinuses at initial presentation are critical as these findings may alter management [79]. Tumors arising from parameningeal sites may produce nasal, aural, or sinus obstruction with or without mucopurulent or sanguineous discharge, but imaging is essential to define parameningeal involvement [80]. Distinguishing parameningeal rhabdomyosarcoma that invades the orbit from a true orbital rhabdomyosarcoma is crucial as this distinction will often influence therapy.

Imaging is essential to the preoperative evaluation of orbital rhabdomyosarcoma to determine tumor location and size and is important in the postoperative phase to evaluate residual or recurrent disease. On CT imaging, rhabdomyosarcomas are frequently seen as a homogeneous orbital mass that is isodense compared to extraocular muscles and often shows contrast enhancement [1, 21, 81]. Although CT may be useful to demonstrate bony destruction [82], MR imaging is the standard of care to evaluate the primary site and the potential for parameningeal disease (Fig. 15.4). On T1-weighted sequences, rhabdomyosarcoma is typically iso- to hyperintense compared to muscle and hypointense compared to orbital fat. On T2-weighted sequences, hypointense, isointense, or hyperintense patterns can be seen. Moderate to marked enhancement with gadolinium is common [1, 21, 83]. PET imaging may also be a valuable adjunct for staging disease [21].

Initially thought to derive from extraocular muscles, rhabdomyosarcoma actually develops from undifferentiated mesenchymal cells that have the capacity to differentiate into striated muscle [75]. The two common histologic subtypes (embryonal and alveolar) have distinct genetic features and prognoses. Embryonal histology is more frequent in orbital rhabdomyosarcoma (84% of cases) and portends better outcomes [84]. Histologically, embryonal rhabdomyosarcoma appears as elongated pleomorphic tumor cells with centrally located hyperchromatic nuclei surrounded by abundant eosinophilic cytoplasm [75]. Alveolar rhabdomyosarcoma has variable histology but most commonly presents as loosely adherent cells attached to a network of thin interstitial fibrovascular septa with many areas of freely floating cells in alveolar-like spaces [75]. Tumors with alveolar histology usually harbor a balanced chromosomal translocation between either PAX3 (from chromosome 2) or PAX7 (from chromosome 1) and FOXO1 (from chromosome 13) creating a fusion transcript PAX-FOXO1. Recent studies suggest that alveolar tumors that lack the PAX-FOXO1 fusion have outcomes similar to embryonal rhabdomyosarcoma [85, 86]. As a result, risk stratification and treatment allocation of rhabdomyosarcoma may rely on fusion status rather than histology in the future.