Journal of Neuro-Ophthalmology, June 2004, Volume 24, Issue 2

Metastatic Neuroblastoma Presenting with Binocular Blindness from Intracranial Compression of the Optic Nerves

A 2-year-old boy with blindness as an isolated symptom was found to have no light perception binocularly because of compression of both optic nerves by a neuroblastoma infiltrating the walls of the optic canals and medial sphenoid bone. Imaging disclosed a primary tumor near the kidney and multiple osseous metastases. Although neuroblastoma commonly causes blindness by metastasis to the orbit, it rarely causes bilateral blindness from intracranial compression of the optic nerves. This is the first report of bilateral blindness as the presenting feature.

ORIGINAL CONTRIBUTION Metastatic Neuroblastoma Presenting with Binocular Blindness from Intracranial Compression of the Optic Nerves Juan J. Chan Lau, MD, Jonathan D. Trobe, MD, Robert E. Ruiz, MD, PhD, Robert W. Cho, MD, Daniel S. Wechsler, MD, Gaurang V. Shah, MD, and Stephen S. Gebarski, MD Abstract: A 2- year- old boy with blindness as an isolated symptom was found to have no light perception binocularly because of compression of both optic nerves by a neuro­blastoma infiltrating the walls of the optic canals and me­dial sphenoid bone. Imaging disclosed a primary tumor near the kidney and multiple osseous metastases. Although neu­roblastoma commonly causes blindness by metastasis to the orbit, it rarely causes bilateral blindness from intracranial compression of the optic nerves. This is the first report of bilateral blindness as the presenting feature. ( JNeuro- Ophthalmol 2004; 24: 119- 124) Several reports ( 1- 13) have documented ophthalmic complications of metastatic neuroblastoma. When vi­sual loss occurs, it is nearly always from optic nerve com­pression by an orbital metastasis causing proptosis ( often ecchymotic) and ductional restriction. We describe a two-year- old boy who presented with binocular blindness from a planum sphenoidale region metastatic neuroblastoma. It compressed both optic nerves as they emerged from the in­tracranial portion of the optic canals. There was no clinical or imaging evidence of orbital invasion. Among the re­ported cases, only one ( 12) is similar to ours. In that case, a 2- year- old boy with antecedent malaise, irritability, and an­orexia eventually developed bilateral blindness from a sphenoidal region neuroblastoma compressing both optic nerves. In that case, no primary tumor was found. CASE REPORT A two- year- old boy reported that he suddenly could not see. His parents had noted that for several days he had Departments of Ophthalmology ( Kellogg Eye Center) ( JCL, JDT), Neurology ( JDT), Pathology ( RER), Pediatrics and Communicable Dis­eases ( RWC, DSW), and Radiology ( GVS, SSG), University of Michigan Medical School, Ann Arbor, Michigan. Address correspondence to Jonathan D. Trobe, MD, Kellogg Eye Cen­ter, 1000 Wall Street, Ann Arbor, MI 48105; E- mail: jdtrobe@ umich. edu been stumbling into objects. During the previous month, he had paid several visits to a pediatrician for fever that led to a diagnosis of otitis media. He was the product of a normal pregnancy and delivery and had no other health problems. Ophthalmic examination verified no light perception in either eye. The globes and their adnexa were normal. There was no proptosis or resistance to retropulsion. The eyes were aligned and moved normally. Pupils measured 7 mm in dim illumination and did not constrict to light. Biomicroscopy and ophthalmoscopy were normal. The rest of his physical examination was unremarkable. Brain magnetic resonance imaging ( MRI) scans ( Figs. 1A, 2A and B, and 3A) showed a heterogeneous mass centered at the level of the planum sphenoidale, per­meating bone, encasing the intracranial optic nerves, and involving the paranasal sinuses and nasopharynx. Signal characteristics suggested neoplasm or unusual infection. The patient was placed on intravenous dexametha-sone. Transnasal biopsy of a left ethmoid mass showed a densely cellular neoplasm composed of small cells with oval to irregular nuclei, granular chromatin, and scant cy­toplasm ( Fig. 4A). One day after the biopsy, the patient still had no vision, so he underwent a transcranial decompres­sion, mainly of the right side of the tumor. A postoperative brain MRI showed moderate decompression of the right op­tic nerve, less so of the left optic nerve ( Figs. IB, 2C, and 3B). Pathologic specimens again showed a small cell neo­plasm forming well- defined nests with abundant associated neuropil, separated by fibrovascular septa, morphologically consistent with a poorly differentiated, Schwannian stroma-poor neuroblastoma with a low mitotic- karyorrhectic index ( Fig. 4B). Immunohistochemical studies showed that the tumor cells were strongly positive for protein gene product 9.5 ( PGP9.5) and negative for MIC- 2, supporting a diagno­sis of neuroblastoma ( Fig. 4C). Bone marrow aspiration re­vealed the presence of metastatic neuroblastoma cells ( Fig. 4D). Computed tomography ( CT) scans of the chest, ab­domen, and pelvis were normal except for a 3 x 2- cm mass J Neuro- Ophthalmol, Vol. 24, No. 2, 2004 119 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Lau et al FIG. 1. A: Preoperative coronal enhanced T1- weighted MRI shows an intensely enhancing soft tissue mass at the ethmoid sinus that permeates the bone and is contiguous intracranially along the planum sphenoidale and posterior orbital roof and elevates the brain. B: Postoperative co­ronal enhanced T1- weighted MRI shows a residual soft tissue mass in the ethmoid region, and at left planum sphenoidale. anterior to the middle pole of the left kidney ( Fig. 5 A). A 123I- metaiodobenzylguanidine ( MIBG) scan showed ab­normal uptake in the left perirenal area and at multiple bony sites, including the spine, pelvis, femur, and humerus. Based on the presence of widespread metastatic disease, a diagnosis of stage 4 neuroblastoma was made, and treat­ment was initiated on the current Children's Oncology Group protocol for high- risk neuroblastoma. Four weeks after the decompression and initiation of chemotherapy, the patient could accurately reach for coins. Both optic discs were slightly pale. An afferent pupil defect was present OS. After five cycles of chemotherapy, the patient under­went laparoscopic resection of the left pararenal mass, most likely arising from a portion of the adrenal gland. Histologic examination revealed a treated neuroblastoma showing a spectrum of apparent differentiation ( Fig. 5B). In addition to chemotherapy and surgery, he has un­dergone an autologous bone marrow transplant, as well as treatment with both 13- cis retinoic acid and 3F8 ( anti- GD2) antibody. Now 18 months from the time of initial diagnosis, the patient remains in clinical remission. Visual acuity is 20/ 400 OD, hand movements OS, with an afferent pupil defect OS and markedly pale optic discs. No additional neuro- ophthalmic deficits have appeared. DISCUSSION The initial clinical manifestation of our young patient with metastatic neuroblastoma was binocular blindness. Vi­sual loss occurs in metastatic neuroblastoma, but it is virtu­ally always based on orbital invasion and is usually monoc­ular. Our case simply represents a more posterior and midline sinocranial deposit that affected the intracranial op­tic nerves bilaterally. In reporting the ophthalmic manifestations of meta­static neuroblastoma, Musarella et al ( 8) found orbital me­tastases in 60 ( 75%) of 80 children. There are four previous reports of neuroblastoma presenting with visual loss but without orbital manifestations ( 4,11- 13). In a retrospective review of 450 neuroblastoma patients, Belgaumi et al ( 4) reported one patient with sudden onset of monocular visual loss without orbital manifestations but no further details are given. In the fourth and fifth editions of Walsh & Hoyt's Clinical Neuro- Ophthalmology, Miller ( 11) described a 22- year- old man who developed progressive monocular optic neuropathy from a neuroblastoma deposited on the sphe­noid bone. Varma et al ( 12) described a two- year- old boy with bilateral blindness because of compression of both op­tic nerves from a neuroblastoma situated in the spheno­ethmoidal region. Their case differs from ours in that the child had premonitory constitutional symptoms of malaise, irritability, and anorexia. In our patient, the visual loss was the only reported or observed manifestation. Shubert et al 120 © 2004 Lippincott Williams & Wilkins Metastatic Neuroblastoma with Binocular Blindness JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 FIG. 2. A: Preoperative axial T2- weighted MRI shows a lowT2- signal mass along the planum sphenoidale and a low signal band of dura separating it from brain parenchyma. B: Preoperative axial enhanced T1- weighted MRI shows intense enhancement of the extradural mass. C: Postoperative axial enhanced T1- weighted MRI shows small enhancing residual mass on the left planum. ( 13) reported a two- year- girl with bilateral blindness and disc edema who also had total left ophthalmoplegia and left upper lid ecchymosis. Autopsy revealed metastatic neuro­blastoma in the anterior and middle fossae compressing both optic nerves and extending through the superior orbital fissure into both orbits. Transverse sinus thrombosis had probably caused elevated intracranial pressure. The pri­mary tumor was suprarenal. Neuroblastoma, the most common extracranial solid tumor of childhood ( 8% of pediatric cancers), arises from cells of the neural crest of any site within the sympathetic nervous system, but an abdominal locus is most common ( 13). Most patients (> 90%) are diagnosed before age 10, the most frequent clinical presentation being that of an ab­dominal mass. Yet up to 50% of patients have metastatic disease at the time of diagnosis. Paraneoplastic manifesta­tions such as opsoclonus- myoclonus or cerebellar ataxia are seen in 4%> of patients. Imaging studies important for stag­ing include CT and MRI, as well as MIBG scanning. Pref­erentially taken up by adrenergic secretory vesicles present FIG. 3. A: Preoperative sagittal enhanced T1 - weighted MRI shows an irregular lobulated mass in the ethmoid region, along the planum sphenoidale, and elevating the frontal lobes anterior to the optic tract. B: Postoperative sagittal unenhanced T1 - weighted MRI shows minimal residual mass along the planum. 121 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Lau et al •;. .*'•** mm FIG. 4. A: Transnasal biopsy of left ethmoid sinus shows a densely cellular neoplasm composed of small cells and associated neuropil, forming sheets and vague nests. The tumor cells occupy the entire respiratory mucosa in this fragment, but respect the epithelium and glandular structures ( hematoxylin and eosin, X200) B: Skull base tumor from craniotomy shows well- defined nests of tumor cells with abundant associated neuropil, separated by fibrovascular septa ( hematoxylin and eosin, X200). C: Immunohistochemical studies show that the tumor cells have strong cytoplasmic reactivity for PGP9.5 ( left, magnification X200) but are negative for CD99 ( MIC- 2) ( right, magnification X200). D: Bone marrow biopsy shows interstitial, sinusoidal, and sheet- like infiltrates of tumor cells occupying much of the intertrabecular space ( hematoxylin and eosin, X200). in neuroblastoma ( and adrenal medullary) cells, MIBG has proven to be a sensitive technique to identify sites of meta­static disease and to evaluate response to treatment ( 14). The initial transnasal biopsies in this case showed a small round cell neoplasm, the differential diagno­sis of which included, in addition to neuroblastoma, non- Hodgkin lymphoma, rhabdomyosarcoma, Ewing sarcoma/ primitive neuroectodermal tumor ( PNET), and esthesioneuroblastoma. Non- Hodgkin lymphoma and rhabdomyosarcoma involving the orbit or paranasal sinuses can present clinically in children as acute bilateral blind­ness ( 15- 17). Ewing sarcoma/ PNET has been reported as a primary neoplasm of skull bones and sinuses ( 17- 22) and also as a metastatic lesion ( 23). A primary Ewing sarcoma/ PNET of the orbit has been associated with unilateral visual loss ( 24). Esthesioneuroblastoma is a much less common tumor, especially in young children, and typically presents with a different set of symptoms ( 25), but presentation with sudden visual loss has been de­scribed ( 26- 28). The subsequent specimens obtained at craniotomy showed tumor cells forming nests with neuropil, providing evidence of neuroectodermal differentiation, which argued against non- Hodgkin lymphoma and rhabdomyosarcoma. The morphologic differential diagnosis could reasonably then be narrowed to neuroblastoma, Ewing sarcoma/ PNET, and esthesioneuroblastoma. Neuroblastoma and Ewing sarcoma/ PNET can show similar morphology. Immunohistochemical studies of PGP9.5 ( 29) and MIC- 2 expression are very helpful in dis- 122 © 2004 Lippincott Williams & Wilkins Metastatic Neuroblastoma with Binocular Blindness JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 FIG. 5. A: Axial enhanced abdominal CT scan of abdomen shows a left para- aortic pararenal soft tissue mass ( arrows) that is possibly the primary site of neuroblastoma. B: Re­section of left pararenal mass after five cycles of chemo­therapy shows neuroblastoma with treatment effect, result­ing in appearances ranging from those of differentiating neuroblastoma ( shown here) to maturing ganglioneuroma ( hematoxylin and eosin, X200). tinguishing between these tumors. Neuroblastoma is typically positive for PGP9.5 and negative for MIC- 2 expression, whereas Ewing sarcoma/ PNET is generally positive for both markers ( 30- 32). In this case, the immunophenotypic profile was that of neuroblastoma. Esthesioneuroblastoma cannot necessarily be ex­cluded morphologically or immunophenotypically. These tumors can show a range of appearances from lesions closely resembling neuroblastoma to lesions resembling neuroendocrine carcinoma ( 33). Distinction from neuro­blastoma can generally be made on clinical grounds. In ad­dition, neuroblastomas differ genetically from esthesion-euroblastomas ( 33). However, if a primary neuroblastoma is not identified elsewhere, and genetic studies are not avail­able, it could be difficult to decide if a sinus mass is best considered a neuroblastoma or an esthesioneuroblastoma. In this case, the subsequent demonstration of an abdominal primary tumor excluded esthesioneuroblastoma. Patients with localized disease ( stages 1, 2) have a better prognosis than those with neuroblastoma that has me­tastasized to distant sites ( stage 4), including bone and bone marrow ( 34). Other features associated with a poor progno­sis are unfavorable histology, amplification of the MYCN oncogene, characteristic chromosomal losses ( lp) and gains ( 17q), age older than one year, and elevated ferritin and urinary catecholamine levels ( 35). Treatment of neuroblastoma involves chemotherapy, surgery, radiation, and autologous bone marrow transplan­tation, which is used as a rescue following marrow- ablative induction chemotherapy. Patients with localized disease have a 95% cure rate; those with intermediate stage neuroblastoma have a 70% o to 80% cure rate; those with advanced disease have only a 20% to 30% cure rate. Recent therapeutic advances include the use of differentiation agents such as 13- cis- retinoic acid in an attempt to improve outcome ( 34). It is thought that retinoic acid causes decreased proliferation, decreased ex­pression of the MYCN oncogene, and morphologic differ­entiation to mature, nondividing cells. In addition, immu­notherapy using the murine 3F8 antibody ( directed against the GD2 surface antigen present on neuroblastoma cells) is undergoing experimental evaluation ( 35,36). Preliminary studies indicate feasibility and efficacy of this novel treat­ment modality. Finally, 131I- MIBG has been used to selec­tively target radiation to residual or recurrent neuroblas­toma in association with myeloablative chemotherapy and hematopoietic stem cell rescue ( 37). 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