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Show Journal of Clinical Neuro- ophthalmo! ogy 12( 1): 31- 36, 1992 {, 1992 Raven Press, Ltd., New York Esthesioneuroblastoma Presenting as Sudden Unilateral Blindness Histopathologic Confirmation of Optic Nerve Demyelination Eric L. Berman, M. D., Alfredo Chu, M. D., Jonathan D. Wirtschafter, M. D., J. Douglas Cameron, M. D., J. Carlos Manivel, M. D., Arndt J. Duvall, M. D., and Stephen J. Haines, M. D. We report here a case of esthesioneuroblastoma an 11year- old girl presenting as acute loss of vision with minimal evidence of orbital, nasal, or paranasal sinus disease, a rare presenting symptom for this tumor. The initial diagnosis was postviral optic neuritis, a pattern of presentation not previously reported. When vision failed to improve, magnetic resonance imaging revealed a lesion in the posterior ethmoid and sphenoid sinuses. After a biopsy, the tumor was excised through the cranium and paranasal sinuses. A mass completely surrounding the optic nerve without invasion was found. Histochemical staining suggested demyelination secondary to compression, confirming the clinical impression of optic neuritis. Anti- Leu 7 monoclonal antibody is useful in characterizing of this tumor, since other immunochemical stains can be misleading. Radiation and chemotherapy were given after the tumor was removed. Two years later, the patient has had neither recurrence nor complications. Key Words: Anti- Leu 7 monoclonal antibodyesthesioneuroblastoma- Postviral optic neuritis. From the Departments of Ophthalmology ( E. L. B., A. C, J. D. W., J. D. C), Laboratory Medicine and Pathology a · eM.), Otolaryngology ( A. J. D.), and Neurosurgery ( S. J. H.), University of Minnesota School of Medicine, Minneapolis, Minnesota, U. S. A. Address correspondence and reprint requests to Dr. Jonathan D. Wirtschafter, Department of Ophthalmology, UMHC Box 493, University of Minnesota, 516 Delaware Street S. E., Minneapolis, MN 55455, U. S. A. . This work was supported in part by unrestncted grants from Research to Prevent Blindness, Inc., New York, New York, and the Minnesota Lions Eye Research Fund. 31 Esthesioneuroblastoma is a neuroectodermal tumor arising from the olfactory mucosa, frequently involving the eye and orbit. This case is unique because its clinical presentation suggested acute demyelination of the optic nerve, and this clinical impression was histologically confirmed when the tumor was found to surround, but not to invade, a demyelinated optic nerve. CASE REPORT The patient was an II- year- old girl who was in good health until she experienced a rapidly progressive loss of vision in the left eye. Three days before the vision loss, she had developed " the flu," conventionally associated with headaches, ocular tenderness, and blurred vision. Over a 24hour period, the visual acuity of the left eye decreased to the point at which there was no light perception. The visual acuity of the unaffected right eye was 20/ 20. There was a left afferent pupillary defect. The anterior segments of both eyes were normal. Both optic discs were well- demarcated with symmetric cup/ disc ratios of 0.4. The maculas appeared normal bilaterally. Extraocular movements were normal. The visual field of the right eye was normal. No other physical or neurologic abnormalities were found. The initial working diagnosis was a probable case of postviral optic neuritis of the left eye. Laboratory results indicated a white blood count of 6,500 with normal differential and a normal erythrocyte sedimentation rate. The patient was observed over a 3- week period, 32 E. L. BERMAN ET AL. and v,' hen the vision failed to improve, imaging studies were performed. A computed tomography ( CT) scan showed destruction of the body of the sphenoid bone pL) sterosuperiorlv, including the margins of the left optic canal. In addition, destruction of the planum sphenoidale on the left side was noted, associated with a broad- based thin intracranial mass. There appeared to be erosion of the lamina papyracea and minimal extension of the mass into the posterior orbit and ethmOid sinuses. The anterior ethmoid cells were not involved. The intracranial portion of the tumor was thought to be extradural and almost certainlv extracerebral. The region of the cribriform plate was not involved ( Fig. 1). Magnetic resonance imaging ( MRI) revealed an abnormal signal within the entire left sphenoid sinus ( Fig. 2). There was slight expansion of the superior and lateral \ valls of the sphenoid and posterior ethmoid sinuses. The left optic nerve appeared slightly compromised by lateral expansion of the sinus into the optic canal and medial wall of the left orbit. The intracranial portion of the optic nerves and chiasm were completely normal. When biopsied, the sphenoid sinus mass was found to be an esthesioneuroblastoma. Because of the circumferential involvement of the optic nerve and its very posterior location, an en bloc resection attempting to achieve tumor- free margins would have had to include such vital structures as the pituitary gland and was therefore not considered. FlG. 1. Coronal bone window CT scan demonstrates destruction of the body of the sphenoid bone includIng part of the left optic canal There is also erosion of the lamina papyracea and minimal extension into the posterior orbit. Considering the age of the patient, lack of metastases, and noninvolvement of the other optic nerve, we decided to perform gross total surgical excision as the primary procedure and to utilize radiation and chemotherapy postoperatively. The cranial vault was entered through a bifrontal approach. The soft tissue was easily identified in the region of the left optic nerve, displacing but not penetrating the overlying dura. The tumor extended from the midline to the limbus sphenoidale and from the anterior c1inoids to the left cavernous sinus. The entire left anterior clinoid and optic canal were totally excised. Because of its proximity to vital structures, the remaining tumor was removed piecemeal. All of the visible tumor was removed from the ethmoid and sphenoid sinuses. Postoperatively, the consensual pupillary light reflex and ocular motility remained normal. A course of radiation therapy, totaling 5,075 cGy, was given to the involved region. Nine courses of chemotherapy ( vincristine and cytoxan) were given. At the most recent examination, 29 months postoperatively, there has neither been evidence of recurrence of tumor nor delayed ophthalmologic complications. The patient's endocrine status is apparently normal. HISTOPATHOLOGICAL FINDINGS Two portions of optic nerve and multiple irregular fragments of bone \,\' ere evaluated. At one end of the larger optic nerve segment, there was a cuff of tissue 13 mm in diameter. The optic nerve parenchvma had undergone mild diffuse swelling and degeneration associated with a mild degree of gliosis. There was no evidence of direct tumor involvement of the optic nerve. Luxol- fast blue stained specimens confirmed demvelination of axons, and Bielscho\\' ski silver stain ~ onfirmed neuroaxonal degeneration ( Figs. 3 and 4). The tumor adjacent to the optic nerve was characterized by sheets of small cells with prominent nuclei and eosinophilic cytoplasm. The cell margins were indistinct. In some areas, the tumor was divided by fibrous septae. Neoplastic cells infiltrated bone and were present immediately beneath respiratory mucosa. There was no histologic evidence of differentiation. There was no fibrillary background nor rosette formation. Immunoperoxidase stains for chromogranin, 5- 100, vimentin, actin, desmin, and neurofilaments were negative. There was faint positivity for Leu 7 and neuronspecific enolase ( Fig. 5). The ultrastructure of the tumor cells was characterized by many cell processes, some of which contained membrane- A ESTHESIONEUROBLASTOMA FIG. 2. Axial ( A) and coronal ( B) MR images without contrast show a mass filling the entire left sphenoid sinus and extending into the left posterior ethmoid sinus. B 33 bound, electron- dense material, consistent with neurosecretory granules ( Fig. 6). Microtubules could be observed in several cell processes. The cytoplasm also contained mitochondria, focally dilated Golgi apparati, and numerous cytoplasmic intermediate filaments. The immunohistochemical and ultrastructural features of neuroblastic differentiation were the basis for the diagnosis of esthesioneuroblastoma. .'" DISCUSSION Esthesioneuroblastoma is a malignant, slow growing, neurogenic neoplasm originating in the olfactory mucosa of the upper nasal cavity ( 1). The neoplasm originates from cells derived from the neural crest ( 2). In the nasal cavity, the usual primary sites include the superior nasal cavity or nasal septum, the turbinates, or the cribriform plate . IJ'... -:. ._. FIG. 3. Luxol- fast blue stain demonstrates demyelination of fibers in the periphery of the nerve. Between arrows x 115. J ( 1m NfllrO- ol'lltlwlmol, Vol. 12, No. 1, 1992 34 E. L. BERMAN ET AL. . .;;... ..., .... ,. .';.'"': '. ~ -- FIG. 4. Bielschowski silver stain shows neuraxonal degeneration ( arrow) in the area corresponding to right arrow of Fig. 3 that is demyelinated; some residual axons are seen in the lower half of the figure. x400. and fovea ethmoidalis ( 2). This neoplasm may also arise as a primary tumor within the paranasal sinuses or intracranially ( 3). In a series of 39 cases, Jackson found a preponderance of women ( 23 in 39) ranging in age from 1 to 65 years in whom the tumor most commonly occurred in the second decade of life ( 2). In contrast to neuroblastomas in other anatomic sites, 01- factory tumors primarily affect adults. This may be related to the fact that the olfactory neuroepithelium, unlike other central neuroectodermal tissue, exhibits continual cellular turnover ( 4). In another series of 48 patients with malignant tumors of the nasal cavity, the ethmoid, and the sphenoid sinuses, eight tumors were found to be esthesioneuroblastoma ( 5). FIG. .5. Immunoperoxidase stains show faint cytoplasmic positivity for neuronspecific enolase ( left) and membrane- based, for leu 7 ( right). ESTHESIONEUROBLASTOMA FIG. 6. The ultrastructure of the tumor cells is characterized by many cell processes, some of which contain microtubules and membrane- bound, electron- dense material consistent with neurosecretory granules ( arrows). The cytoplasm also contains mitochondria, focally dilated Golgi apparati, and numerous cytoplasmic intermediate filaments x 38,700. 35 The neoplasm is noted for its variability of clinical presentation ( 6). Because esthesioneuroblastorna is usually derived from the lining of nasal cavities and paranasal sinuses, the presenting symptoms often include nasal obstruction and congestion, epistaxis, facial numbness and swelling, diplopia, ocular pain, proptosis, or headaches ( 2). The tumor may present as an inflammatory nasal polyp ( 7). In a Mayo Clinic series, 28 of 38 cases were associated with ophthalmic signs or symptoms at some time during the course of the disease. Of the 28 cases, ophthalmic signs were manifested when the neoplasm was initially diagnosed in 20 cases. Signs and symptoms included periorbital pain, excessive tearing, eyelid edema, proptosis, globe injection, and ptosis. Five of these patients presented with coexisting ophthalmic, but not visual, complaints ( 8). Patients may rarely present with visual abnormalities. Two such cases have been reported: in one, intracranial extension from a sphenoid or ethmoid sinus produced purulent meningitis associated with blindness ( 9); the other patient developed loss of vision 6 months after developing anosmia ( 10). The reported incidence and extent of metastasis of esthesioneuroblastoma has been variable ( 11). The sites of distant metastasis include cervical lymph nodes, bones, soft tissue, and brain ( 7,12,13). Tumor cells may be distributed by the cerebrospinal fluid to such remote sites as the posterior fossa ( 13) and even the cauda equina ( 6). Metastasis may be delayed as in the case reported by Rodas ( 11) in which metastatic disease developed in the right parietal cortex and meninges 5 years after surgical and radiotherapeutic treatment of a primary lesion. No convincing relationship has been shown between histologic appearance and behavior ( 2). Computed tomography most often shows esthesioneuroblastoma to be a soft tissue mass that adheres to the cribriform plate, usually with bone lysis ( 1). Two cases have been reported in which hyperostosis was present ( 1). Magnetic resonance imaging with multislice Tl- weighted images is useful for showing tumor extension into paranasal sinuses. Increasing degrees of T2- weighting allow the tumor to be differentiated from fluid retention secondary to compression of the normal sinus orifices ( 14). Scintigraphy has also been used to identify the tumor ( 15). Light microscopy shows that cytologic features include uniform, small, round- to- oval cells with coarsely granular chromatin, multiple small nucleoli, prominent nuclear membranes, and scant cytoplasm ( 12). A prominent fibrillary background is often present. The neuroblasts are occasionally ar- J Clill Neuro- ophthalmol. Vol. 12. No. 1. 1992 36 E. L. BERMAN ET AL. ranged into both rosettes of the Homer- Wright type and pseudorosettes although the tumor cells may show axon production ( 16), differentiation into mature ganglion cells does not take place. The cytologic appearance of tumor cells in cerebrospinal tluid may be misinterpreted as anaplastic carcinoma, rhabdomyosarcoma, melanoma, and nonHodgkins lymphoma ( 6). Ultrastructural characteristics include dense core secretory granules in the cytoplasm and cell processes ( 12,17). The dendritic processes contain microtubuli and filaments as well as secretory granules of 1800A. The production of dense core granules is the most characteristic ultrastructural feature ( 16). Anti- Leu 7 monoclonal antibody recognizes a protein originally identified in natural- killer cells; however, this protein is also present in most neoplasms of neuroectodermal origin and can be helpful as part of a battery of immunostains ( 18) in the differential diagnosis of these tumors. It is important to use a carefully designed battery of immunostains in the differential diagnosis of olfactory neuroblastomas because reactivity for other markers, such as leukocyte common antigen, 5- 100 protein, and HMB- 45, or desmin and actin would identify a small cell tumor of this anatomic region as a lymphoma, small cell melanoma, or rhabdomyosarcoma, respectively. Esthesioneuroblastoma is clearly aggressive and needs to be treated accordingly ( 6). Many centers now consider chemotherapy to be the treatment of choice, either with or without surgical intervention ( 19). Vincristine and cytoxan sometimes supplemented by doxorubicin is the usual regimen. Early lesions without signs of metastases may be treated surgically in the hope of achieving a definite cure. Metastatic lesions are usually treated by chemotherapy alone. In a series of 26 cases reported by Willen ( 7), there was a 37.5% survival for nonaggressively treated cases compared to 82% with more aggressive multi- agent chemotherapy. Highdose chemotherapy and autologous bone marrow transplantation was used in 26 patients to treat advanced disease ( 20). Preoperative and postoperative radiation therapy has been used routinely with good results. Preoperative treatment has not affected postoperative healing ( 21). In a recent study, it was found that radiation therapy is complicated by blindness in 33% of cases ( 5). One study showed that longterm survival could be linked to orbital or cervical lymph node involvement on initial presentation ( 22). The patient described in this article appears to follow that trend, doing well 2 years after surgery without signs of recurrence. REFERENCES 1 Regenbogen VS. Zinreich SJ, Kim KS. et al. Hyperostotic esthesioneuroblastoma: CT and MR findmgs. J Comput As-sist Tomogr 1988; 12: 52-<:;. . 2. 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