Ординатура / Офтальмология / Английские материалы / Orbital Tumors Diagnosis and Treatment_Karcioglu_2005

with rapidly progressive proptosis and displacement of the globe. The mass usually occurs in the superior orbit because of the tendency of this tumor to arise from the supraorbital and supratrochlear nerve.30,31 However, MPNST can occur in other orbital locations (Figure 17.6A, B).31 Unlike benign orbital peripheral nerve tumors, they are more likely to be accompanied by pain, ptosis, and signs of optic nerve compression, which reflect the rapidly progressive nature of this tumor.30,31

MPNST has a tendency to develop perineural spread, resulting in orbital recurrence and intracranial invasion. Orbital recurrence is usually associated with

A

metastasis. Metastasis from orbital MPNST usually occurs to the regional lymph nodes and the lung.30,31 Metastasis usually develops within the first 2 years after diagnosis.30

Malignant triton tumor is a sarcomatous variant of the MPNST showing areas of skeletal muscle differentiation. It can occur in the orbit. Triton tumor has a strong association with neurofibromatosis, is very aggressive in growth and has a high rate of metastasis.33

Radiologic Features

On CT, malignant peripheral nerve sheath tumors generally have ill-defined irregular borders. There may be adjacent bone invasion.30,31

Morphologic Features

Grossly, the MPNST is an ill-defined gray-white lesion with a nodular configuration. Pathologically, there is usually no capsule,31 although in rare instances the tumor appears to be encapsulated.32 The tumor is composed of spindle-shaped cells with nuclear pleomorphism, hyperchromatism, and mitotic figures (Figure 17.6C). Occasionally, epithelioid cells and multinucleated giant cells are present.30,31 The nerve of origin in MPNST is evident in 50% of the cases.8

With S-100, MPNST shows positive immunoreactivity that is less uniform and focal than in schwannoma. Transmission electron microscopy demonstrates prominent nucleoli suggesting a malignant tumor. The presence of long-spacing extracellular collagen (Luse bodies) suggesting a Schwann cell origin has not been convincingly demonstrated in all MPNSTs.30,31

B

C

FIGURE 17.6. Malignant schwannoma in a 67-year-old patient. (A) Axial CT shows that the tumor occupies the anterior and middle orbit (arrows). (B) Coronal CT demonstrates that the malignant schwannoma occupies the superior and inferior orbit (arrows). (C) Histopathologic examination shows that malignant peripheral nerve sheath tumor is a highly cellular tumor composed of spindle cells with nuclear pleomorphism and hyperchromatism (H&E, original magnification 200).

Management and Prognosis

Treatment of MPNST consists of total excision of the soft tissue tumor. Adjacent bone should be removed if there is bone invasion. The risk of metastasis increases if the patient develops orbital recurrence. Therefore, it is important to obtain clear margins at the time of initial surgery to reduce the risk of metastasis. If this is not possible or documentable, some authors have suggested an aggressive approach consisting of exenteration and radiotherapy (50–60 Gy).30,31 Others recommend continued observation with serial neuroimaging studies after complete excision of the orbital tumor.32 Chemotherapy has been used in patients with distant metastasis, but there is no substantial evidence that it is effective.30,31

The prognosis for survival in patients with MPNST of the orbit appears to be poor. In one series, 9 of 13 patients with orbital MPNST were deceased within 5 years after diagnosis.31

Clinical Features

Orbital GCT usually occurs in adult patients, although it can also occur in children.36,41 The age range of the patients with orbital GCT at the time of diagnosis is between 341 and 7436 years. However, the majority of the patients are 40 to 60 years old. There is no distinguishing feature for periorbital GCT. Most patients present with a slowly growing orbital or eyelid tumor resulting in proptosis, ptosis, or diplopia (Figure 17.7A).35–38,42 The tumor is attached to the orbicularis or rectus muscle in about 25% of the cases.36 Orbital GCT can lead to dilation of the epibulbar vessels in the quadrant(s) where the tumor is located.

A malignant variant of GCT with metastatic potential has been reported.39 Primary malignant GCT is rare in the orbit. However, histopathologically benign orbital GCT can demonstrate invasion into the adjacent tissues.37

Radiologic Features

Computed tomography shows that orbital GCT can present as a well-circumscribed orbital mass (Figure 17.7B),35,36,38 or as an ill-defined mass infiltrating the posterior orbit.37 The tumor may be attached to an extraocular muscle. As such, orbital GCT is indistinguishable from other well-circumscribed or ill-defined orbital tumors in neuroimaging studies.35–39

Morphologic Features

The excised orbital GCT can be well circumscribed or ill defined. It is yellow-gray in color. The well-

B

C

D

FIGURE 17.7. A 65-year-old woman with orbital granular cell tumor. (A) Facial photograph showing the motility restriction of the right eye in right gaze owing to the location of the tumor in the temporal orbit. (B) Axial CT showing the extraconally located orbital granular cell tumor in close association with the lateral rectus muscle (arrow). (C) Histopathologic examination demonstrates that the tumor is composed of round cells with granular eosinophilic cytoplasm and small nuclei. The tumor cells lie in a collagenous tissue stroma (H&E, original magnification 400). (D) Transmission electron micrograph shows that the cytoplasm of tumor cells are filled with several membrane-bound inclusions.

circumscribed tumor appears to have a capsule.35 Microscopically, the tumor is composed of lobules of round or oval cells with a granular eosinophilic cytoplasm and small nuclei.35–37,42 The tumor cells are arranged in clusters or fascicles between strands of collagenous tissue or skeletal muscle cells (Figure 17.7C). With immunostaining, the tumor is positive for neural markers including S-100 protein, neuron-specific enolase (NSE), and various myelin proteins.35–37,39,42 The positive immunoreactivity with S-100 protein provides support for the Schwann cell origin of this tumor.36

Transmission electron microscopy shows that the cytoplasm of tumor cells are filled by numerous mem- brane-bound cytoplasmic inclusions that are the ultrastructural counterpart of granularity noted histopathologically (Figure 17.7D). These inclusions contain cellular debris including mitochondria, myelin figures, rough endoplasmic reticulum, and residual axons.36,37

Management and Prognosis

The best treatment for orbital GCT is surgical excision.35,36 For infiltrative tumors, complete surgical excision may be difficult.37 Orbital GCT is radioresistant.42 Exenteration probably should be employed only in recurrent tumors.41 The visual and systemic prognosis for patients with orbital GCT is good if the tumor is completely excised.41

ALVEOLAR SOFT PART SARCOMA

Alveolar soft part sarcoma (ASPS) is a malignant tumor of the soft tissues in which the cells are arranged in an alveolar pattern, from which the name of the tumor is derived. It most often develops in the buttocks and thighs, being closely related to skeletal muscles.43 ASPS can rarely occur in the orbit (Table 17.1).44–49 There is considerable overlap between orbital granular cell tumor, alveolar soft part sarcoma, and paragangliomas reported in the earlier literature. Many cases reported as granular cell tumor or paraganglioma have been shown after careful pathologic examinations, to be ASPS.

Clinical Features

The ages of the patients reported in the literature range from 11 months to 69 years, with a median of approximately 18 years.44 Females are affected more often than males. Most patients present with rapidly progressive proptosis. In some instances the tumor presents with eyelid swelling and in others as an epibulbar mass. When the tumor is located anteriorly in the orbit, dilated epibulbar blood vessels in the

quadrant(s) of the tumor may be evident.44,47 ASPS may secondarily involve the orbital bone and soft tissues from the nasal cavity and paranasal sinuses.

ASPS has a tendency to metastasize to the lungs, bone, and brain.44 Prognosis is variable depending on the completeness of surgical excision and tumor histopathology. Patients with completely resected tumors appear to have a better prognosis than those whose tumors have been incompletely resected.

Radiologic Features

CT images reveal that the tumor is usually well circumscribed.45,47 The tumor generally occupies an anterior position in the orbit where it is attached to one of the extraocular muscles. In some cases, it may be located deep in the orbit and appears ill defined on neuroimaging studies.

Morphologic Features

On gross examination, the tumor is pink or red, generally well circumscribed, but in some cases ill defined. In some cases, the tumor appears to be encapsulated.44 The tumor cells are arranged in an alveolar pattern similar to metastatic renal cell carcinoma. The tumor cells are polygonal or rounded and have a large cytoplasm with eccentrically placed nuclei and prominent nucleolus.44,45 An important finding of ASPS is the presence in the cytoplasm of tumor cells of diastase-resistant crystalline structures that elicit a positive reaction to the periodic acid–Schiff (PAS) stain. These crystals have never been demonstrated in any other neoplasm. Therefore, their presence is considered to be highly characteristic and virtually diagnostic of ASPS.44 In contrast to most peripheral nerve tumors of the orbit, the tumor stains negative for S- 100 protein.45

Management and Prognosis

Wide surgical excision is the treatment of choice for ASPS. Tumors located anteriorly in the orbit in close association to an extraocular muscle can be completely excised.45,47,49 Tumors located deep in the orbit that cannot be excised completely are treated with exenteration. Supplemental external beam radiation therapy (50–60 Gy) has been used in patients with incompletely resected tumors or recurrences.44,47

Based on the limited literature data, orbital ASPS seems to have better systemic prognosis than nonorbital lesions. In a report of 17 patients with orbital ASPS, 11 were alive at follow-ups ranging from 4 to 16 years.44 Two patients died from tumor metastasis at intervals of 14 and 21 years after treatment. Two patients died from causes unrelated to the tumor, and 2 patients were lost to follow-up.

PARAGANGLIOMA

Paraganglioma, also known as chemodectoma, is a benign and uncommon tumor of paraganglion cells (glomus bodies). Paraganglion cells are of neural crest origin. This tumor usually occurs in the head and neck region but can also occur in the thorax and abdomen. The most common site of origin is the carotid body, followed by jugulotympanic and vagal paragangliomas.50 In the orbit, paraganglioma is a rare tumor (Table 17.1). Orbital paraganglioma is believed to arise from the ciliary ganglion, ciliary nerve, or related neural tissue.50 Multiple paragangliomas can occur in 10 to 20% of the patients. Paragangliomas may occur simultaneously in the orbit and carotid body.51

It has been speculated that the development of carotid body paragangliomas may be related to higher altitudes ( 2000 m) and accompanying hypoxia.52 All paragangliomas contain neurosecretory granules in their cytoplasm. However, only 1 to 3% of paragangliomas are clinically functional and secrete norepinephrine. Functional paragangliomas are usually located in the adrenal glands. Paragangliomas at other locations including the orbit are usually nonfunctional and do not secrete norepinephrine.50

Clinical Features

In 13 cases that have been reported in the literature by Archer and associates, the ages of the patients ranged between 3 and 68 years.51 The patient with orbital paraganglioma most frequently develops proptosis.51 The tumor is generally attached to an extraocular muscle, causing motility restriction. Tumors located in the anterior orbit may lead to dilation of episcleral blood vessels.52 In the differential diagnosis of dilated episcleral blood vessels, orbital tumors including granular cell tumor, alveolar soft part sarcoma, and paraganglioma should be considered. Paraganglioma may also occur deep in the orbit in the region of the ciliary ganglion.51,53 In such cases, the tumor may present with diplopia, papilledema, and decreased vision.51,53

About 5 to 10% of all paragangliomas are malignant. Malignant paragangliomas can demonstrate local invasion and metastasis. Metastasis usually occurs to distant organs or to regional lymph nodes.50

Radiologic Features

Orbital CT and MR images demonstrate a wellcircumscribed tumor that may be attached to a rectus muscle.53 In some cases, the tumor may appear illdefined, occupying the posterior orbit.51 In most cases, there is no orbital bone involvement. However, rarely a malignant orbital paraganglioma can demonstrate orbital bone destruction.51 Malignant paragangliomas of the nasal cavity and paranasal sinuses can also secondarily invade the orbit through the medial orbital wall.

Morphologic Features

Grossly, the paraganglioma is usually well circumscribed. Rarely, it can also be ill defined. The lesion is pink. Histopathologically, there is no true capsule. The tumor is composed of clusters of cells sometimes called zellballen, which are separated from one another by delicate septae that contain blood vessels. The cells are polygonal, with round to oval nuclei. Mitosis is uncommon.52,53

The PAS reaction is useful in the differentiation of paraganglioma from ASPS because ASPS contains PAS-positive cytoplasmic crystalline inclusions; however, paraganglioma is PAS negative. In ASPS, immunostaining is positive for neuron-specific enolase (NSE).52,53 Transmission electron microscopy reveals membrane-bound neurosecretory granules.53

Management and Prognosis

The best treatment of orbital paraganglioma is total surgical excision. Tumors located anteriorly in the orbit may be amenable to total excision. However, those located deeper in the orbit in the region of the ciliary ganglion may be treated with incisional biopsy followed by external beam radiation therapy (50 Gy).51 Orbital paraganglioma is generally radiosensitive,51,55 although in rare instances it does not respond to external beam radiation therapy.54 Radical orbital surgery such as exenteration should be withheld until definite signs of orbital recurrence or malignant transformation are noted.

Metastasis can develop at follow-up periods ranging from a few months to as long as 42 years.55 Therefore, given the long interval between the primary tumor and metastases, these patients require extended follow-up.

AMPUTATION NEUROMA

Orbital amputation neuroma is a rare tumor (Table 17.1). Amputation (traumatic) neuroma occurs at the proximal stump of severed peripheral nerves in the orbit. Amputation neuroma develops after orbital surgery, usually enucleation,56,57 but it can also develop after strabismus surgery58 and orbital bone fractures.59 Following transection of a peripheral nerve, axonal sprouting characterized by proliferating Schwann cells, fibroblasts, and axons starts at the proximal stump. This proliferative activity represents an attempt of the proximal nerve to establish continuity with its distal counterpart. If there is a large defect that cannot be bridged, or if the distal segment has been removed, an amputation neuroma results. Orbital amputation neuromas are not known to arise from the optic nerve.

Clinical Features

The amputation neuroma usually manifests as a painless orbital mass, many months after orbital surgical procedures or trauma.56–59 If the enucleation was performed for a malignant intraocular tumor, the possibility of orbital recurrence is usually the first diagnostic consideration.

Although a higher frequency of amputation neuromas following orbital surgery or trauma may be expected, these tumors have rarely been reported in the literature. Many neuromas arising from the small severed peripheral nerves do not reach a large enough size to be clinically detectable. The amputation neuroma rarely causes pain, hence is usually asymptomatic.

Radiologic Features

Orbital CT shows a well-circumscribed mass in an anophthalmic socket.57,59 Amputation neuroma may occur in association with a conjunctival implantation cyst.57 The cysts seen on CT in two cases were confirmed histopathologically to be adjacent conjunctival implantation cysts. Their relationship to the amputation neuroma is unclear, but they are probably coincidental.57

Morphologic Features

Grossly, the amputation neuroma presents as a circumscribed white-gray mass. There is no capsule. Microscopically, the mass is composed of proliferated axons, Schwann cells, and fibroblasts.57 The presence of distinct perineurium helps to differentiate this lesion from a plexiform neurofibroma. The typical clinical history and the absence of neurofibromatosis also are helpful in making this distinction.

Management and Prognosis

The recommended management of orbital amputation neuroma is surgical excision of the mass and orbital reconstruction if necessary. A dermis fat graft or a mucous membrane graft may be required for orbital reconstruction.57 Since the tumor is benign with no malignant potential, the systemic prognosis of the patient with an orbital amputation neuroma is excellent.

mor generally occurs in infants under 1 year of age. Melanotic neuroectodermal tumor is probably of neural crest origin.61,63

Clinical Features

The child with melanotic neuroectodermal tumor in the zygomatic bone develops a mass on the face with medial displacement of the eye. Since the mass is related to the bone, it is usually hard and immobile to palpation.64 There is no pain or eyelid ecchymosis, features that would help to differentiate it from a metastatic neuroblastoma. Elevated serum vanilmandelic acid level has been reported in patients with melanotic neuroectodermal tumor. Other laboratory studies are normal.60,61

In nonorbital locations, local recurrence develops in 10 to 45% of the patients and metastasis is about 3%.60,61 Periorbital tumors appear to have a better prognosis. In a report of six cases, recurrence was noted in one patient (16%). None of the patients developed malignant transformation and metastasis.62

Radiologic Features

Orbital CT imaging reveals a lytic lesion in the lateral orbital wall with sclerosis of the adjacent bone.

Morphologic Features

On gross examination, the tumor is ill-defined and is gray to blue-black, depending on the melanin content. Light microscopy reveals two cell types: small poorly differentiated cells and larger pigmented cells. The small poorly differentiated cells are probably of neuroblastic origin. The pigmented cells bear a striking similarity to the retinal pigment epithelium in the eye. Immunohistochemical staining is positive for epithelial, melanocytic, and neural markers. Transmission electron microscopy demonstrates electron-dense granules in the cytoplasm of the pigmented cells.61,63

Management and Prognosis

The management consists of total excision. The prognosis of the patient with melanotic neuroectodermal tumor is generally good provided the tumor is adequately resected.60–62 The patient should be followed closely, however, for signs of possible recurrence and metastasis.

MELANOTIC NEUROECTODERMAL TUMOR OF INFANCY

The melanotic neuroectodermal tumor of infancy, or retinal anlage tumor, is a benign pigmented lesion that frequently involves the head and neck region.60,61 The tumor usually originates in the anterior portion of the maxillary bone, but it rarely arises from the zygomatic bone, producing orbital manifestations.60–62 This tu-

PRIMARY ORBITAL NEUROBLASTOMA

Primary orbital neuroblastoma is very rare. Orbital involvement in neuroblastoma is usually secondary or metastatic. Secondary orbital neuroblastoma develops from orbital invasion of olfactory neuroblastoma (esthesioneuroblastoma). Metastatic orbital neuroblas-

toma originates from the adrenal medulla, retroperitoneum, and mediastinal and cervical sympathetic ganglia and spreads hematogenously to the orbit.64 There has been only one well-documented case of primary orbital neuroblastoma, diagnosed in a 49-year- old woman in whom no other primary lesion could be found.65 Over 12 years, the patient underwent five local excisions, external beam radiation therapy to the orbit, and finally orbital exenteration. Computed tomography performed before orbital exenteration demonstrated an ill-defined mass filling the entire orbit.65

Histopathologic examination of the tumor in this case showed spindle cells with benign cytologic features, no mitotic activity, palisading of the nuclei, and Homer–Wright rosettes. Immunohistochemical staining was positive for NSE but negative for glial fibrillary acidic protein (GFAP). Transmission electron microscopy demonstrated the presence of electron dense neurosecretory granules in the cytoplasm.65

Primary orbital neuroblastoma is unlikely to be diagnosed clinically or radiologically. It is difficult to make any treatment recommendations based on this single case in the literature. It is best to remove the orbital tumor totally. If this is not possible, external beam radiation therapy or exenteration can be employed for the residual tumor.

PRIMARY ORBITAL

CARCINOID TUMOR

Carcinoid tumors arise from the enterochromaffin system (Kultschitzsky cells). They usually occur in the appendix, ileum, and bronchi. Carcinoid tumors of gastrointestinal origin are more likely to metastasize to the orbit, whereas bronchial carcinoids are more likely to metastasize to the uvea.66

Although the majority of orbital carcinoid tumors represent metastatic foci, the following reported case is believed to be a true primary orbital carcinoid tumor. A 71-year-old woman presented with a slowly progressive proptosis of 11 years’ duration.67 The affected eye had been blind for 4 years at the time of presentation. Orbital CT disclosed an infiltrative tumor with ill-defined borders. The orbit was exenterated. Histopathologic examination showed that the tumor was composed of small cells with round or oval hyperchromatic nuclei arranged in solid lobules and rosettelike configuration in some areas. Cytoplasmic neurosecretory granules were demonstrated by transmission electron microscopy. These findings were found to be consistent with the diagnosis of carcinoid tumor. Urinary level of 5-hydroxyindolacetic acid was normal. No primary tumor was found. There was no orbital recurrence or metastasis 15 years after orbital exenteration according to the latest follow-up data.11

Primary orbital carcinoid tumor is unlikely to be

diagnosed clinically and by imaging studies. An attempt should be made to excise the orbital tumor completely. After the diagnosis of orbital carcinoid is made, it is appropriate to make a systemic evaluation looking for a primary site. If the results of the systemic evaluation are negative, the residual orbital tumor should be treated with external beam radiation therapy. The radiation dose for metastatic orbital carcinoid tumor is around 40 Gy, so a similar dose may also be appropriate for primary orbital carcinoid tumor.64

NEUROFIBROMATOSIS

Neurofibromatosis, an oculoneurocutaneous syndrome characterized by multisystem involvement, can lead to a wide variety of clinical symptoms and signs.68 There are two distinct subtypes of neurofibromatosis. Neurofibromatosis type 1 (NF1) affects about 1 in 4000 individuals, and neurofibromatosis type 2 (NF2) affects about 1 in 50,000.69

NF1 is also known as peripheral neurofibromatosis or von Recklinghausen’s syndrome. It is characterized by many peripheral cutaneous manifestations and is recognized to occur from an abnormality of chromosome 17.68 The gene responsible for the development of this disorder is called NF1. NF2 is called central or bilateral acoustic neurofibromatosis. It is characterized by central neural tumors and early onset of posterior subcapsular cataract and is recognized to be related to an abnormality in chromosome 22.69 The gene for this disorder is called NF2. Both forms of neurofibromatosis are transmitted by an autosomal dominant mode of inheritence.

Although the penetrance of both NF1 and NF2 is greater than 95%, the expressivity of the disease is highly variable.68,70 Some patients have only a mild form of the disease and others a severe form of the disease.68 The gene for NF1 encodes a protein termed neurofibromin, and the gene for NF2 encodes a protein termed merlin or schwannomin. Both proteins have tumor suppressor activity, downregulating the activity of proto-oncogenes.70–72

Although there is considerable overlap between NF1 and NF2, the ophthalmic manifestations are discussed separately. The diagnostic criteria for NF1 and NF2 are given in Boxes 17.1 and 17.2. Strict criteria should be met before the diagnosis of neurofibromatosis is made.

Ophthalmic Manifestations of

Neurofibromatosis Type 1

Ophthalmic involvement in NF1 include abnormalities in the uveal tract (80%), eyelid (25%), cornea (25%), optic nerve (12%), retina (9%), and conjunctiva (4%).73

BOX 17.1. Diagnostic Criteria for Neurofibromatosis Type 1

Presence of two or more of the following criteria: Café-au-lait macules, six or more ( 5 mm in diameter in prepubertal individuals and 15

mm in postpubertal individuals) Neurofibromas, two or more of any type, or

one plexiform neurofibroma

Freckling in the axillary or inguinal regions Optic gliomas

Lisch nodules, two or more

Distinctive osseous lesion (sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis)

First-degree relative with neurofibromatosis type 1 by the foregoing criteria

EYELIDS

Patients with NF1 may develop café-au-lait spots, fibroma molluscum (dermal neurofibromas), and plexiform neurofibroma in the eyelids. The first two conditions may not produce visual problems, but plexiform neurofibroma results in the typical S-shaped curvature of the upper eyelid, a finding that is believed to be highly characteristic of neurofibromatosis. In about 25% of the patients with eyelid plexiform neurofibroma, the tumor extends to involve the orbit.73 The eyelid plexiform neurofibroma is treated by surgical debulking, and frontalis suspension procedures are necessary to reduce ptosis.

ORBIT

Proptosis may be observed in NF1 and may occur from a variety of reasons: optic nerve glioma or rarely meningioma, orbital tumors including neurofibroma or schwannoma, and bony defects in the greater wing of the sphenoid.68 Bony defects in the greater wing of the sphenoid enable the pulsations of brain to be transmitted to the orbit, resulting in proptosis. The tumor that is most characteristic of NF1 is optic nerve glioma. Other tumors are more rarely seen than optic nerve glioma.

The optic nerve can be involved with pilocytic astrocytoma (glioma) or meningioma. In patients with pilocytic astrocytoma, the reported incidence of neurofibromatosis has ranged from 9 to 30%.22 Juvenile pilocytic astrocytoma of the optic nerve is a slowly progressive lesion that can lead to proptosis (Figure 17.8A), optic disk edema (Figure 17.8C), retinal venous obstruction, optic atrophy, and visual loss. Optociliary (or retinochoroidal) shunt vessels, a characteris-

tic finding in optic nerve sheath meningioma, occur rarely with optic glioma (Figure 17.8C).

Gliomas may either involve the intraorbital portion of the optic nerve or the chiasm and optic tracts. In the majority of cases, optic nerve gliomas are selflimited or grow very slowly. Tumors located to the optic nerve at the time of diagnosis infrequently extend into the chiasm subsequently.74,75 Some studies indicate that optic nerve gliomas associated with NF1 carry a more benign prognosis than those unassociated with NF176; other studies failed to disclose such a relationship.74

Diagnosis of optic nerve glioma is usually based on orbital imaging. In CT and MR images, optic nerve glioma appears as oval or fusiform enlargements of the optic nerve (Figure 17.8D). Increased length of the intraorbital nerve segment results in kinking of the optic nerve. Optic nerve meningioma, in contrast, tends to produce a “railroad track” appearance. MRI is generally considered to be superior to CT for demonstrating the optic nerve features and showing the extent of intracranial disease. In patients with NF1, optic nerve glioma may rupture through the pia surrounding the optic nerve and proliferate in the subarachnoid space. This manifests on MRI as arachnoidal hyperplasia surrounding the optic nerve (Figure 17.8D, inset).

Observation is generally recommended if there is no clinical or radiographic evidence of progression of an optic nerve glioma.75 If the patient has chiasmal involvement that threatens to extend into surrounding structures resulting in progressive visual loss, hydrocephalus, or other serious complications, surgical excision or radiotherapy can be employed.77 Complete surgical excision may not be possible in many extrachiasmal cases. External beam radiation therapy (40–50 Gy) is used either alone or after incomplete excision in such cases.77

EXTRAOCULAR MUSCLES

Congenital absence of the superior oblique tendon and inferior rectus muscle have been reported in patients with NF1.78,79

BOX 17.2. Diagnostic Criteria for Neurofibromatosis Type 2

Bilateral eighth nerve masses (acoustic neuromas) or

First-degree relative with neurofibromatosis type 2 and

Unilateral eighth nerve mass or

Two of the following: neurofibroma, schwannoma, glioma, meningioma, juvenile posterior subcapsular cataract

FIGURE 17.8. A 5-year-old boy with NF1 and bilateral optic nerve gliomas. (A) Facial photograph demonstrating downward proptosis of the left eye. (B) Anterior segment photograph showing multiple Lisch nodules located on the anterior iris surface (arrows). (C) Fundus photograph of the left eye showing optic disk edema and op-

CONJUNCTIVA

The conjunctiva may rarely be involved by neurofibromas in a patient with NF1.73

ANTERIOR SEGMENT

Iris melanocytic hamartoma, known as Lisch nodules, is the most common uveal abnormality, occurring in nearly 80% of the patients with NF1.73 Lisch nodules are small, sharply demarcated, dome-shaped, lightly pigmented lesions on the anterior surface of the iris (Figure 17.8B). The finding of two or more Lisch nodules is a diagnostic criterion for NF1, but often dozens of them are present. They usually become apparent around age 5 years. Unlike iris nevi, the nodules are raised and have a gelatinous appearance. Histologically, Lisch nodules are focal aggregates of melanocytes and glial cells on the anterior border layer of the iris. Another anterior segment finding in NF1 is the presence of enlarged corneal nerves.73

GLAUCOMA

Unilateral congenital glaucoma appears to occur more commonly in patients who have neurofibromatous in-

tociliary shunt vessel (arrow). (D) Axial orbital T1-weighted MR image showing bilateral optic nerve gliomas isointense to the extraocular muscle and cerebral gray matter (arrows). Inset: Coronal orbital T1-weighted MR image demonstrating bilateral arachnoidal hyperplasia surrounding the optic nerve gliomas (arrows).

volvement of the eyelids. The most important cause of glaucoma is the obstruction of aqueous outflow by diffuse neurofibromatous thickening of the trabecular meshwork.80 Glaucoma may also develop from maldevelopment of the anterior chamber angle, angle closure due to forward displacement of the iris by a ciliary body tumor, or iris neovascularization.80 Medical treatment of this type of glaucoma is uniformly unsuccessful. Surgical options include goniotomy, filtering procedures, cyclocryotherapy, and cyclophotocoagulation. However, the long-term prognosis is quite poor.

RETINA AND CHOROID

Hamartomas similar to those that occur in the iris can also occur in the choroid of patients with neurofibromatosis. The choroidal lesion is similar histopathologically to the iris lesion and probably represents a nevus.73

Other patients with neurofibromatosis have a diffuse thickening of the uveal tract, which can be difficult to recognize on clinical examination. This uveal thickening probably results from the proliferation of neurofibromatous (Schwann cells and in

some cases ganglions) and melanocytic elements.81 Other choroidal tumors that can occur in patients with neurofibromatosis are choroidal melanoma and neurilemoma (schwannoma).82,83 Choroidal melanoma and neurilemoma are managed with one of several methods including enucleation, local resection, plaque radiotherapy, and transpupillary thermotherapy.

Retinal manifestations in NF1 that require no treatment include retinal astrocytic hamartoma, myelinated nerve fibers, multifocal congenital hypertrophy of the retinal pigment epithelium, retinal hamartoma (i.e., phakomatosis) similar to the combined pigment epithelial and retinal hamartoma, and retinal vascular occlusions (retinal vein and arterial occlusions).73,84 The vascular occlusions probably develop from the proliferating Schwann cells in the vascular walls occluding the vessels.

Ophthalmic Manifestations of NF2

The three major ocular manifestations of NF2 are juvenile posterior subcapsular or cortical cataracts (69%), retinal hamartomas (22%), and ocular motor abnormalities (12%). The subcapsular and cortical cataract in patients with NF2 usually develops before age 30 years. Ocular motor palsies are due either to the presence of a tumor or to increased intracranial pressure.85

In another report focusing on the posterior segment findings of NF2, the most frequent retinal finding was an epiretinal membrane observed in 80% of the patients.86 Additionally, a lesion similar to the combined pigment epithelial and retinal hamartoma was observed in 7% of the patients.86 Epiretinal membranes, which do not generally develop in patients with NF1, are observed in patients with NF2.86 The retinal hamartoma resembles the combined pigment epithelial and retinal hamartoma in some respects. However, the retinal hamartoma may also represent an atypical lesion consisting of an epiretinal membrane associated with a retinal glial hamartoma similar to the one seen in tuberous sclerosis. If the retinal glial hamartoma is too small initially to be detectable on funduscopy the lesion may be observed as an epiretinal membrane.86 It is speculated that cells of neural crest origin at the vitreoretinal juncture and in the retina proliferate or develop abnormalities resulting in epiretinal membrane and retinal hamartoma. Similar changes occurring in the ectodermal cells of the lens result in cataract.86

Other rare ophthalmic manifestations of NF2 include Lisch nodules,85 pseudopapilledema caused by epiretinal membrane extending onto the optic disk,87 papilledema from increased intracranial pressure,88 optic nerve glioma and optic nerve sheath meningioma,85 and morning glory disk abnormality.89

Systemic Features of Neurofibromatosis

The most common cutaneous manifestations of neurofibromatosis include pigmented macules (café- au-lait spots), axillary and inguinal freckling, benign nerve sheath tumors (most commonly neurofibroma but also schwannoma), and nevi.68 Most of these skin lesions become clinically apparent at puberty, although some instances have been noted at birth. Café- au-lait spots are highly characteristic of neurofibromatosis seen in 94 to 100% of patients with NF1.68 Axillary and inguinal freckling is seen in approximately 67% of the patients.68 The benign cutaneous and subcutaneous nerve sheath tumors (neurofibromas and schwannomas) are particularly pronounced in the facial area.

The pigmented macule (café-au-lait spot) is characterized as a patch of light brown pigmentation with fairly well-defined borders. It can occur anywhere on the skin and can assume a variety of size and configurations. Approximately 25% of the normal population can have one to three café-au-lait spots. However, patients with neurofibromatosis have more and larger café-au-lait spots.68

The central nervous system manifestations of neurofibromatosis vary with the size and the extent of the associated tumors. Acoustic neuromas, particularly if bilateral, are considered to be pathognomonic of NF2. Other associated tumors include gliomas in the region of the third ventricle, pituitary tumors, and spinal cord meningiomas.68,81

Some patients with NF1 develop seizure disorder and mild intellectual impairment. Bright lesions seen on T2-weighted MRI may represent brain dysplasia or heterotopias. The significance of these bright lesions in relation to seizure disorder and intelligence problems is not known.68

Skeletal abnormalities are common in patients with NF1. Vertebral defects and scoliosis can occur. An uncommon problem is the development of pseudoarthroses (false joints). Pseudoarthroses result from thinning of long bones, fractures, and abnormal callus formation.68

Other benign and malignant systemic tumors that have been associated with neurofibromatosis include neurofibrosarcoma, pheochromocytoma, breast carcinoma, genitourinary tumors, gastrointestinal tumors, and cutaneous melanoma. Patients with neurofibromatosis are recognized to have a slightly higher incidence of pheochromocytoma.68,81

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