OPTIC N E R V E GLIOMA IN AN 18-MONTH-OLD CHILD HIROHIKO M I K I , M.D.,
AND ASAO HIRANO,
M.D.
Bronx, New York During a 15-year period, Collins and Marshall1 found only two cases of optic nerve glioma among 388,000 outpatients examined. Optic nerve glioma is responsi ble for 6% of all tumors found within the orbital region2 and for 1% of intracranial tumors.3 This glioma occurs commonly in children: 75% of the patients in another study were less than 10 years old.4 Thus, Hudson 5 and Verhoeff6'7 advocated the possi bility of a congenital origin of glioma. Recently, Luse 8 and Anderson and Spen cer9 studied the ultracytologic structure of an optic nerve glioma. They described be nign optic nerve gliomas that were com posed of fibrous astrocytes and connective tissue septa, or sometimes mucoid material. The conspicuous features of the cytoplasm were abundant glial fibrils and especially prominent Rosenthal fibers within long tumor processes with sparse organelles. Hamilton and associates10 described a malig nant optic nerve glioma in which the cells were rich in organelles, particularly dilated cisternae of the endoplasmic reticulum and prominent Golgi apparatus. The cytoplasmic processes were short and stubby and contained delicate filaments arrayed in whorls as well as Rosenthal fibers. The endothelia of numerous capillaries were hyperplastic and bulged into the vessel lumen. Since one of the most interesting factors From the Department of Ophthalmology (Dr. Miki) and the Department of Pathology (Dr. Hirano), Montefiore Hospital and Medical Center/ Albert Einstein College of Medicine, Bronx, New York. This study was supported in part by Public Health Service grant EY00613-4; Fight for Sight, Inc., New York; Research to Prevent Blindness; and Seeing Eye, Inc., Morristown, New Jersey. Dr. Miki is an International Research Scholar of Re search to Prevent Blindness, Inc. Reprint requests to Hirohiko Miki, M.D., De partment of Ophthalmology, Kansai Medical School, Fumizono-cho, Moriguchi, Osaka, Japan.
in optic nerve glioma has been the question of its origin and development, we examined a younger patient with optic nerve glioma ultracytologically. We have examined a large solid optic nerve glioma from an 18mpnth-old child, which is, as far as we are aware, the youngest examined by both light and electron microscopy. CASE REPORT
An 18-month-old patient was admitted with a history of proptosis and exotropia of the right eye of 12 months' duration. The left pupil was of nor mal size and promptly reacted to light, but the right pupil was somewhat large and showed a de fective light response. The extraocular movements of the right eye were slightly limited in all direc tions, and moderately limited in the superior direc tion. An ophthalmometer (Hertel) showed the right eye to be proptosed 3 or 4 mm. An ophthalmoscopic examination showed that the margin of the right optic disk was hazy with slightly dilated veins. The left fundus was normal. The remainder of the ocular examination was unremarkable. The only abnormality shown in series of roentgenograms of the skull was that the right optic canal was twice its normal size with an intact margin. General physical examination, laboratory studies, and electrocardiogram were normal. Skin signs such as café-au-lait spots were not found on the patient or his parents. A diagnosis of optic nerve glioma was made. The tumor was removed by the modified Krönlein approach from just behind the globe without enucleation. So far, the patient has survived two years with no evidence of recurrence. MATERIALS
A N D METHODS
Immediately after excision, the tumor mass was placed in 10% formaldehyde and prepared for light microscopy. Several pieces of the tumor mass from different re gions were put in Karnovsky's fixative,11 followed by 1% osmium postfixation, de hydrated in a graded series of ethyl alcohol, cleared in propylene oxide, and embedded in Epon. T h i n sections for electron micro scopy were stained with uranyl acetate and lead citrate and examined in a Zeiss E M 9 S - 2 electron microscope.
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Fig. 1 (Miki and Hirano). A portion of the tumor. Tumor tissue is composed mostly of astrocytes that are char acterized by spindleshaped cells with ovoid nuclei and partly of con nective tissue (hematoxylin and eosin, χ250).
RESULTS
Gross findings—The removed tumor mass was a smooth, solid, well-defined, ellipsoid mass, 1.7 X 3.0 cm in size. Light microscopy—The histologie fea tures of this tumor were typical of a benign astrocytoma. The cells were characterized by the presence of plump, spindle-shaped cells with ovoid nuclei, indicating the possi bility of a fibrous astrocytoma that was con firmed using electron microscopy. No mitotic figures or pleomorphic nuclei were ob served (Fig. 1). Electron microscopy—A majority of the cellular elements of this tumor were astrocytes referred to as fibrous, since the most prominent cytoplasmic components of this tumor are the numerous fibrils that occur throughout the perikaryon and extend as parallel arrays into the processes. Most pro cesses of the tumor emerged from the cell body in a radial direction, particularly longer in the longitudinal direction of the optic nerve, and occupied most of the tumor mass (Fig. 2 ) . The nuclei were large, round, or elliptical in shape and showed a few coarse clumps of chromatin within a
relatively light karyoplasm (Fig. 2). The usual organelles occur sparsely in the cyto plasm of the tumor cells. These organelles are mainly confined to the perikaryal re gion where they are interspersed with the fibrils. The cell processes contain a varying amount of glycogen. A pair of centrioles in the cytoplasm of a tumor cell was also seen. They show a 9 + 0 pattern with electrondense halo outside and inside, and oriented with their long axes perpendicular to each other (Fig. 3). Some microtubules were also seen among the fibrils in a majority of tumor processes. They have an outside diameter of about 20 nm with a central density core of ap proximately S nm in diameter (Fig. 4 ) . Most conspicuous in the tumor cell pro cesses were dense, osmiophilic, homoge neous, carrot-shaped or beaded masses re ferred to as Rosenthal fibers (Fig. 5). These Rosenthal fibers were found together with dense deposits which appeared to be calcium (Fig. 6 ) . In other places, Rosenthai fibers and the electron-dense calcium deposits were located separately. No evi dence of myelin breakdown was found.
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Fig. 2 (Miki and Hirano). Optic nerve glioma. The tumor is composed of compactly arranged tumor cell processes (TP) and perikarya filled with microfilaments. A nucleus (N) shows relatively light karyoplasm (X6.000).
Desmosome-like intercellular adhesions were present between adjacent tumor cells. Connective tissue deeply indented the tumor and partially separated it into funiculi. The septa of the connective tissue were composed of well-packed collagen fibers, fibroblasts, and small vessels derived from the piai system. Fibroblasts had a moderately dilated, rough surfaced endo plasma; reticulum in the cytoplasm. Most blood vessels found in the collagenfilled connective tissue of the septa showed nonfenestrated endothelial cells held to gether by tight junctions. However, some of the capillaries had fenestrae of the vascu lar endothelium. These small pores were about 50 nm in diameter and separated the lumen from the perivascular connective space by a thin diaphragm (Fig. 7). A basement membrane (basement lamina) surrounded the endothelium of the small vessels and capillaries, as well as the side of the astrocytic process facing the connective tissue septa.
the youngest described and the glioma is larger than those previously reported. The histologie appearance of this tumor, despite
DISCUSSION
Optic nerve glioma commonly occurs in children.1'4·12 The patient in this report is
Fig. 3 (Miki and Hirano). A centriole in the cytoplasm of a tumor cell (X 90,000).
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Fig. 4 (Miki and Hirano). Glialfilamentsvirtually fill the cytoplasm of the tumor cell processes (TP) In addition, microtubules (arrows) and mitochondria (M) are seen (χ45,000). the young age of the patient, is similar to the benign and slowly growing astrocytic gliomas reported in older patients by An derson and Spencer9 and Luse.8 The criteria for a slow-growing, benign optic nerve glioma are considered to be the presence of Rosenthal fibers, calcium-like, electron-dense deposits as well as a relative abundance of microfilaments. Rosenthal fibers have generally been recog
nized as a common finding in optic nerve glioma (astrocytoma) and in astrocytoma of the brain. They are not peculiar to astro cytic tumors, occur in various pathologic processes where a reactive gliosis is part of a long-standing process, and indicate dis ordered astrocyte metabolism.13'26 Numer ous calcium-like deposits are usually indica tive of long-standing processes in neo plasms.
Fig. 5(Miki and Hirano). Rosenthal fibers (RF) are surrounded by numerous glial filaments (X21.000).
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wm4 Fig. 6 (Miki and Hirano). Electron-dense calcium-like deposits (CA) are found in close association with Rosenthal fibers (RF) (X28.000). In normal astrocytes of the optic nerve, the relationship of microtubules to microfilaments changes with development. At birth most astrocytic processes contain only microtubules. As maturation proceeds, the microtubules decrease in number and are replaced by the typical astrocytic fibrils. Normal mature optic nerve astrocytes con tain only a few microtubules among the fibrils in the cytoplasm.27"29 Although the light microscopic appearance of this glioma is similar to that found in long-standing re active gliosis, there is no evidence of tissue
atrophy which always accompanies gliosis. To the contrary, the large size of the tumor mass suggests that this glioma is a true neo plasm. In conclusion, our findings seem to sup port Hudson, 5 Verhoeff,6·7 and Davis80 who have hypothesized that optic nerve glioma is a congenital and benign tumor. The blood vessels in normal optic nerve have been described as nonfenestrated vessels joined by tight junctions,28·29 and the blood vessels in optic nerve glioma9 have also been described as nonfenestrated
Fig. 7 (Miki and Hirano). Some capillaries within the collagen-filled connective tissue (CT) had fenestrated endothelial cells. A pore (arrow) can be seen separating the vessel lumen (LUMEN) from the perivascular space ( x 39,000).
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York, Harper and Row, 1963, p. 167. 3. Russell, D. S., and Rubinstein, L. J. : Tumours of the Optic Nerve. Glioma. Pathology of Tu mours of the Nervous System, 3rd ed. London, Arnold. 1971, p. 230. 4. Chutorian, A. M., Schwartz, J. R, Evans, R. A., and Carter, S. : Optic giiomas in children. Neurology 14:83, 1964. 5. Hudson, A. C. : Primary tumors of the optic nerve. Roy. Ophthalmol. Hosp. Rep., 18:317, 1912. 6. Verhoeff, F. H. : Primary intraneural tumors (giiomas) of the optic nerve. Arch. Ophthalmol 51:120, 1922. 7. : Tumors of the optic nerve. In Penfield, W. (ed.) : Cytology and Cellular Pathology of the Nervous System. New York, Hoeber, Inc., 1932, p. 1029. 8. Luse, S. A. : An electron microscopic study of normal optic nerve and of an optic nerve glioma. J. Neurosurg. 18:466, 1961. 9. Anderson, D. R. and Spencer, W. H. : Ultrastructural and histochemical observation of op:ic nerve giiomas. Arch. Ophthalmol. 83:324, 1970. 10. Hamilton, A. M., Garner, A., Tripathi, R. C, and Sanders, M. D. : Mnlignant optic nerve glioma. Br. J. Ophthalmol. 57:253, 1973. 11. Karnovsky, M. J. : A formaldehyde-glutaraldehyde fixative of high osmolnrity for use in electron microscopy. J. Cell. Biol. 27:137a, 1965. 12. Hoyt, W. F.. and Baghdassarian, S. A.: Optic glioma of childhood. Br. J. Ophthalmol. 53: 793, 1969. 13. Bucy, P. C, and Gustafson, W. A. : Struc ture, nature and classification of cerebellar astrocytomas. Am. J. Cancer 35:327, 1939. 14. Grcevic, N., and Yates, P. O. : Rosenthal fibers in tumours of the central nervous system. J. Pathol. Bact. 73:467, 1957. 15. Duffell, D., Färber, L., Chou, S., Hartmann, SUMMARY J. F., and Nelson, E. : Electron mi~roscop:c obser An optic nerve glioma in an 18-month- vations on astrocytomas. Am. J. Pathol. 43:539, 1963. old child was examined by both light and 16. Srh'ote W : Rose"th-
AND ASAO HIRANO,
M.D.
Bronx, New York During a 15-year period, Collins and Marshall1 found only two cases of optic nerve glioma among 388,000 outpatients examined. Optic nerve glioma is responsi ble for 6% of all tumors found within the orbital region2 and for 1% of intracranial tumors.3 This glioma occurs commonly in children: 75% of the patients in another study were less than 10 years old.4 Thus, Hudson 5 and Verhoeff6'7 advocated the possi bility of a congenital origin of glioma. Recently, Luse 8 and Anderson and Spen cer9 studied the ultracytologic structure of an optic nerve glioma. They described be nign optic nerve gliomas that were com posed of fibrous astrocytes and connective tissue septa, or sometimes mucoid material. The conspicuous features of the cytoplasm were abundant glial fibrils and especially prominent Rosenthal fibers within long tumor processes with sparse organelles. Hamilton and associates10 described a malig nant optic nerve glioma in which the cells were rich in organelles, particularly dilated cisternae of the endoplasmic reticulum and prominent Golgi apparatus. The cytoplasmic processes were short and stubby and contained delicate filaments arrayed in whorls as well as Rosenthal fibers. The endothelia of numerous capillaries were hyperplastic and bulged into the vessel lumen. Since one of the most interesting factors From the Department of Ophthalmology (Dr. Miki) and the Department of Pathology (Dr. Hirano), Montefiore Hospital and Medical Center/ Albert Einstein College of Medicine, Bronx, New York. This study was supported in part by Public Health Service grant EY00613-4; Fight for Sight, Inc., New York; Research to Prevent Blindness; and Seeing Eye, Inc., Morristown, New Jersey. Dr. Miki is an International Research Scholar of Re search to Prevent Blindness, Inc. Reprint requests to Hirohiko Miki, M.D., De partment of Ophthalmology, Kansai Medical School, Fumizono-cho, Moriguchi, Osaka, Japan.
in optic nerve glioma has been the question of its origin and development, we examined a younger patient with optic nerve glioma ultracytologically. We have examined a large solid optic nerve glioma from an 18mpnth-old child, which is, as far as we are aware, the youngest examined by both light and electron microscopy. CASE REPORT
An 18-month-old patient was admitted with a history of proptosis and exotropia of the right eye of 12 months' duration. The left pupil was of nor mal size and promptly reacted to light, but the right pupil was somewhat large and showed a de fective light response. The extraocular movements of the right eye were slightly limited in all direc tions, and moderately limited in the superior direc tion. An ophthalmometer (Hertel) showed the right eye to be proptosed 3 or 4 mm. An ophthalmoscopic examination showed that the margin of the right optic disk was hazy with slightly dilated veins. The left fundus was normal. The remainder of the ocular examination was unremarkable. The only abnormality shown in series of roentgenograms of the skull was that the right optic canal was twice its normal size with an intact margin. General physical examination, laboratory studies, and electrocardiogram were normal. Skin signs such as café-au-lait spots were not found on the patient or his parents. A diagnosis of optic nerve glioma was made. The tumor was removed by the modified Krönlein approach from just behind the globe without enucleation. So far, the patient has survived two years with no evidence of recurrence. MATERIALS
A N D METHODS
Immediately after excision, the tumor mass was placed in 10% formaldehyde and prepared for light microscopy. Several pieces of the tumor mass from different re gions were put in Karnovsky's fixative,11 followed by 1% osmium postfixation, de hydrated in a graded series of ethyl alcohol, cleared in propylene oxide, and embedded in Epon. T h i n sections for electron micro scopy were stained with uranyl acetate and lead citrate and examined in a Zeiss E M 9 S - 2 electron microscope.
589
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AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL, 197S
Fig. 1 (Miki and Hirano). A portion of the tumor. Tumor tissue is composed mostly of astrocytes that are char acterized by spindleshaped cells with ovoid nuclei and partly of con nective tissue (hematoxylin and eosin, χ250).
RESULTS
Gross findings—The removed tumor mass was a smooth, solid, well-defined, ellipsoid mass, 1.7 X 3.0 cm in size. Light microscopy—The histologie fea tures of this tumor were typical of a benign astrocytoma. The cells were characterized by the presence of plump, spindle-shaped cells with ovoid nuclei, indicating the possi bility of a fibrous astrocytoma that was con firmed using electron microscopy. No mitotic figures or pleomorphic nuclei were ob served (Fig. 1). Electron microscopy—A majority of the cellular elements of this tumor were astrocytes referred to as fibrous, since the most prominent cytoplasmic components of this tumor are the numerous fibrils that occur throughout the perikaryon and extend as parallel arrays into the processes. Most pro cesses of the tumor emerged from the cell body in a radial direction, particularly longer in the longitudinal direction of the optic nerve, and occupied most of the tumor mass (Fig. 2 ) . The nuclei were large, round, or elliptical in shape and showed a few coarse clumps of chromatin within a
relatively light karyoplasm (Fig. 2). The usual organelles occur sparsely in the cyto plasm of the tumor cells. These organelles are mainly confined to the perikaryal re gion where they are interspersed with the fibrils. The cell processes contain a varying amount of glycogen. A pair of centrioles in the cytoplasm of a tumor cell was also seen. They show a 9 + 0 pattern with electrondense halo outside and inside, and oriented with their long axes perpendicular to each other (Fig. 3). Some microtubules were also seen among the fibrils in a majority of tumor processes. They have an outside diameter of about 20 nm with a central density core of ap proximately S nm in diameter (Fig. 4 ) . Most conspicuous in the tumor cell pro cesses were dense, osmiophilic, homoge neous, carrot-shaped or beaded masses re ferred to as Rosenthal fibers (Fig. 5). These Rosenthal fibers were found together with dense deposits which appeared to be calcium (Fig. 6 ) . In other places, Rosenthai fibers and the electron-dense calcium deposits were located separately. No evi dence of myelin breakdown was found.
OPTIC NERVE GLIOMA
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591
Fig. 2 (Miki and Hirano). Optic nerve glioma. The tumor is composed of compactly arranged tumor cell processes (TP) and perikarya filled with microfilaments. A nucleus (N) shows relatively light karyoplasm (X6.000).
Desmosome-like intercellular adhesions were present between adjacent tumor cells. Connective tissue deeply indented the tumor and partially separated it into funiculi. The septa of the connective tissue were composed of well-packed collagen fibers, fibroblasts, and small vessels derived from the piai system. Fibroblasts had a moderately dilated, rough surfaced endo plasma; reticulum in the cytoplasm. Most blood vessels found in the collagenfilled connective tissue of the septa showed nonfenestrated endothelial cells held to gether by tight junctions. However, some of the capillaries had fenestrae of the vascu lar endothelium. These small pores were about 50 nm in diameter and separated the lumen from the perivascular connective space by a thin diaphragm (Fig. 7). A basement membrane (basement lamina) surrounded the endothelium of the small vessels and capillaries, as well as the side of the astrocytic process facing the connective tissue septa.
the youngest described and the glioma is larger than those previously reported. The histologie appearance of this tumor, despite
DISCUSSION
Optic nerve glioma commonly occurs in children.1'4·12 The patient in this report is
Fig. 3 (Miki and Hirano). A centriole in the cytoplasm of a tumor cell (X 90,000).
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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Fig. 4 (Miki and Hirano). Glialfilamentsvirtually fill the cytoplasm of the tumor cell processes (TP) In addition, microtubules (arrows) and mitochondria (M) are seen (χ45,000). the young age of the patient, is similar to the benign and slowly growing astrocytic gliomas reported in older patients by An derson and Spencer9 and Luse.8 The criteria for a slow-growing, benign optic nerve glioma are considered to be the presence of Rosenthal fibers, calcium-like, electron-dense deposits as well as a relative abundance of microfilaments. Rosenthal fibers have generally been recog
nized as a common finding in optic nerve glioma (astrocytoma) and in astrocytoma of the brain. They are not peculiar to astro cytic tumors, occur in various pathologic processes where a reactive gliosis is part of a long-standing process, and indicate dis ordered astrocyte metabolism.13'26 Numer ous calcium-like deposits are usually indica tive of long-standing processes in neo plasms.
Fig. 5(Miki and Hirano). Rosenthal fibers (RF) are surrounded by numerous glial filaments (X21.000).
VOL. 79, NO. 4
OPTIC NERVE GLIOMA
wm4 Fig. 6 (Miki and Hirano). Electron-dense calcium-like deposits (CA) are found in close association with Rosenthal fibers (RF) (X28.000). In normal astrocytes of the optic nerve, the relationship of microtubules to microfilaments changes with development. At birth most astrocytic processes contain only microtubules. As maturation proceeds, the microtubules decrease in number and are replaced by the typical astrocytic fibrils. Normal mature optic nerve astrocytes con tain only a few microtubules among the fibrils in the cytoplasm.27"29 Although the light microscopic appearance of this glioma is similar to that found in long-standing re active gliosis, there is no evidence of tissue
atrophy which always accompanies gliosis. To the contrary, the large size of the tumor mass suggests that this glioma is a true neo plasm. In conclusion, our findings seem to sup port Hudson, 5 Verhoeff,6·7 and Davis80 who have hypothesized that optic nerve glioma is a congenital and benign tumor. The blood vessels in normal optic nerve have been described as nonfenestrated vessels joined by tight junctions,28·29 and the blood vessels in optic nerve glioma9 have also been described as nonfenestrated
Fig. 7 (Miki and Hirano). Some capillaries within the collagen-filled connective tissue (CT) had fenestrated endothelial cells. A pore (arrow) can be seen separating the vessel lumen (LUMEN) from the perivascular space ( x 39,000).
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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York, Harper and Row, 1963, p. 167. 3. Russell, D. S., and Rubinstein, L. J. : Tumours of the Optic Nerve. Glioma. Pathology of Tu mours of the Nervous System, 3rd ed. London, Arnold. 1971, p. 230. 4. Chutorian, A. M., Schwartz, J. R, Evans, R. A., and Carter, S. : Optic giiomas in children. Neurology 14:83, 1964. 5. Hudson, A. C. : Primary tumors of the optic nerve. Roy. Ophthalmol. Hosp. Rep., 18:317, 1912. 6. Verhoeff, F. H. : Primary intraneural tumors (giiomas) of the optic nerve. Arch. Ophthalmol 51:120, 1922. 7. : Tumors of the optic nerve. In Penfield, W. (ed.) : Cytology and Cellular Pathology of the Nervous System. New York, Hoeber, Inc., 1932, p. 1029. 8. Luse, S. A. : An electron microscopic study of normal optic nerve and of an optic nerve glioma. J. Neurosurg. 18:466, 1961. 9. Anderson, D. R. and Spencer, W. H. : Ultrastructural and histochemical observation of op:ic nerve giiomas. Arch. Ophthalmol. 83:324, 1970. 10. Hamilton, A. M., Garner, A., Tripathi, R. C, and Sanders, M. D. : Mnlignant optic nerve glioma. Br. J. Ophthalmol. 57:253, 1973. 11. Karnovsky, M. J. : A formaldehyde-glutaraldehyde fixative of high osmolnrity for use in electron microscopy. J. Cell. Biol. 27:137a, 1965. 12. Hoyt, W. F.. and Baghdassarian, S. A.: Optic glioma of childhood. Br. J. Ophthalmol. 53: 793, 1969. 13. Bucy, P. C, and Gustafson, W. A. : Struc ture, nature and classification of cerebellar astrocytomas. Am. J. Cancer 35:327, 1939. 14. Grcevic, N., and Yates, P. O. : Rosenthal fibers in tumours of the central nervous system. J. Pathol. Bact. 73:467, 1957. 15. Duffell, D., Färber, L., Chou, S., Hartmann, SUMMARY J. F., and Nelson, E. : Electron mi~roscop:c obser An optic nerve glioma in an 18-month- vations on astrocytomas. Am. J. Pathol. 43:539, 1963. old child was examined by both light and 16. Srh'ote W : Rose"th-
