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Arch Ophthalmol. 2004;122:1712-1714.

Ganglioneuromas are rare benign neoplasms of neuroblastic origin that have been reported in multiple anatomic locations. Orbital involvement is extremely rare, with only a single reported case of direct extension to the orbit from an adjacent parasinus. This is the first reported case of a ganglioneuroma arising in the orbit.

Report of a Case
A 12-year-old African American male had progressive proptosis of the right eye during a 1-year period (Figure 1). The child had a history of stage IV neuroblastoma 10 years earlier that had originated in the adrenal gland and was treated with 7 courses of cyclophosphamide and teniposide after induction with adriamycin and cyclophosphamide. Neuroblastoma with metastases was confirmed by biopsy of the adrenal gland prior to induction of chemotherapy. No additional surgery was performed because of the advanced stage of the disease, and the patient responded to chemotherapy and remained in remission. His past medical history also included multiple cutaneous ganglioneuromas of the abdomen and gastrointestinal ganglioneuromas. He was profoundly mentally handicapped since infancy. Eye examination revealed no light perception in both eyes. He had 4 mm of proptosis of the right eye. His pupils were slowly reactive to light with no afferent pupillary defect. The cornea of the right eye evidenced diffuse punctate epithelial erosions and moderate conjunctival injection. Results of an anterior segment examination of the left eye were normal. Ductions were full in both eyes. Dilated funduscopic examination revealed optic nerve pallor with cup to disc ratio of 0.6 in both eyes. The macula, retina, and vitreous were normal in both eyes.

View larger version (90K): [in this window] [in a new window] Figure 1. Clinical photograph prior to surgery showing proptosis of the right eye.

Magnetic resonance imaging revealed a lobulated neoplasm of the right superior orbit that molded around the globe (Figure 2 and Figure 3). The neoplasm was enhanced with contrast and appeared homogeneous in composition. There was no evidence of involvement of the bone. Orbital exploration via an anterior orbitotomy incision revealed a circumscribed lesion with a gray-tan surface without necrosis (Figure 4). Histopathologic examination of an incisional biopsy revealed neural tissue containingmature ganglion cells, and no neuroblastic elements were pres-ent. Because of progressive proptosis and corneal exposure, debulking was performed. Extensive histologic sampling revealed the neoplasm to be composed entirely of mature ganglioneuromatous tissue; again, no foci of neuroblastoma or sarcoma were detected (Figure 5). Immunohistochemical stains showed ganglion cells exhibiting strong cytoplasmic positivity for neuron-specific enolase and synaptophysin; only occasional ganglion cells demonstrated weak positivity for neurofilament and S-100 protein. The spindle cell component of the neoplasm demonstrated strong cytoplasmic positivity for S-100 protein, neurofilament, synaptophysin, and neuron-specific enolase. The immunohistochemical findings are consistent with ganglioneuroma.¹

View larger version (73K): [in this window] [in a new window] Figure 2. Axial view of an orbital T1-weighted magnetic resonance image revealing a superior orbital neoplasm.

View larger version (98K): [in this window] [in a new window] Figure 3. Coronal view of an orbital T1-weighted magnetic resonance image showing a neoplasm without invasion of the bone.

View larger version (66K): [in this window] [in a new window] Figure 4. Gross photograph of the neoplasm showing a circumscribed lesion with a variegated tan-white surface lacking necrosis.

View larger version (110K): [in this window] [in a new window] Figure 5. Hematoxylin-eosin staining showing mature ganglion cells within a neurofibrillary matrix and no neuroblastoma (original magnification x 200).

Comment
Neuroblastic neoplasms can be broadly subcategorized as neuroblastoma, ganglioneuroblastoma, or ganglioneuroma.² Ganglioneuromas are benign neoplasms composed of neural elements, including mature ganglion cells. Grossly, ganglioneuromas appear circumscribed with a gray or tan cut surface having a whorled appearance on sectioning. In addition to its association with metastatic neuroblastoma, ganglioneuroma has been associated with neurofibromatosis type 1³ and multiple endocrine neoplasia.⁴ Ganglioneuromas of the gastrointestinal tract are not uncommon in the neurofibromatosis. They also commonly arise from the sympathetic chain and can be found in the retroperitoneum or posterior mediastinum.⁵ A single orbital case has been documented that described local extension from the sinuses.⁶ Metastases do not occur; however, patients who have had metastatic neuroblastoma may develop ganglioneuromas that are thought to represent rests of neuroblastoma cells that have undergone differentiation to ganglioneuromas.⁷ These neoplasms are rare compared with other neurogenic lesions, such as neurofibroma and schwannoma. To our knowledge, ours represents the first case of ganglioneuroma arising in the orbit.

Ganglioneuromas may arise de novo or in patients who have had chemotherapy for metastatic neuroblastoma. Typically, they enlarge slowly; rapid growth should raise suspicion for a poorly differentiated neoplasm. Neoplasms of primitive neuroectodermal origin, such as neuroblastoma, contain pluripotent cells that have the capacity to differentiate into mature cellular elements, such as ganglion cells.⁸ When ganglion cell differentiation is present within an otherwise typical neuroblastoma, the term ganglioneuroblastoma is appropriate. In the present case, clinical uncertainty regarding cellular composition coupled with progressive proptosis and its associated corneal complication prompted debulking of the lesion. The history of metastatic neuroblastoma and the presence of multiple ganglioneuromas lend credence to the theory purporting the presence of rests of metastatic neuroblastoma that subsequently undergo maturation. Ganglioneuromas, as fully differentiated neoplasms, do not have the capability to metastasize, so extensive surgical resections or chemotherapy is not normally necessary, provided surgical sampling is sufficient to allow adequate histologic analysis and to assure no neuroblastic cellular elements are present. Excision may be considered when the pathologic diagnosis is uncertain or visual function is compromised by the neoplasm.

AUTHOR INFORMATION
Correspondence: Dr Cannon, University of Arkansas for Medical Sciences, Jones Eye Institute, 4301 W Markham, Slot 523, Little Rock, AR 72205 (tomccannon{at}aol.com).

Financial Disclosure: None.

Funding/Support: This study was supported in part by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY.

Thomas C. Cannon, MD; Harry H. Brown, MD; Bradley M. Hughes, MD; Alyssa N. Wenger, MD; Steven B. Flynn, MD, PhD; Christopher T. Westfall, MD

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