Aeta neuropath. (Berl.) 31, 181--189 (1975) 9 by Springer-Verlag 1975 Originalarbeiten
9 Original
Investigations
9 Travaux
originaux
Intracranial Esthesioneuroblastoma A L i g h t and Electron M i c r o s c o p i c S t u d y S y d n e y S. Schochet, Jr., B r u c e Peters, J o h n O'Neal, a n d W i l l i a m F. McCormick Division of Neuropathology, Department of Pathology, Department of Neurology and Division of Neurosurgcry, Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77550 Received August 29, 1974; Accepted December 18, 1974
Summary. A 31 year-old black woman with unilateral facial dysesthesia was found to have an intracranial parasellar mass that extended into the sphenoid sinus. By light microscopy, the neoplasm appeared as nests of poorly differentiated neuroblasts in a finely fihrillary stroma and was diagnosed as an esthesioneuroblastoma. Electron microscopy confirmed the neuroblastic nature of the tumor with demonstration of neurites containing neurofilaments and neurotubnles, synapses and dense cored biogenic amine granules in perikarya and processes. This neoplasm was further characterized by the presence of numerous dystrophic axons that were evident only by electron microscopy. Key words: Esthesioncuroblastoma -- Neuroblastoma -- Biogenic Amine Granules -Dystrophic Axons.
Introduction E s t h e s i o n e u r o b l a s t o m a s are well k n o w n b u t r e l a t i v e l y rare neurogenic t u m o r s t h a t u s u a l l y arise in t h e n a s a l c a v i t y a n d p r e s e n t clinically with nasal o b s t r u c t i o n a n d epistaxis ( F i t z - H u g h et al. ; Lewis et al. ; Castro et al.). A few cases h a v e been r e p o r t e d in w h o m t h e t u m o r was m a n i f e s t e d i n i t a l l y as a n i n t r a c r a n i a l mass ( H a m i l t o n et al.). The i n t r a c r a n i a l t u m o r s are histologically i d e n t i c a l to t h e m o r e usual e s t h e s i o n e u r o b l a s t o m a s from t h e n a s a l cavities. B o t h t y p e s m u s t be distinguished from m e t a s t a t i c n e u r o b l a s t o m a s from e x t r a c r a n i a l sites a n d from t h e so-called p r i m a r y cerebral n e u r o b l a s t o m a s . W e arc a w a r e of o n l y two r e p o r t s describing t h e u l t r a s t r u c t u r e of e s t h e s i o n e u r o b l a s t o m a s , b o t h b a s e d on specimens f r o m t h e n a s a l cavities ( M c G a v r a n ; K a h n ) . The p r e s e n t r e p o r t describes t h e e l e c t r o n microscopic findings in a n esthesion e u r o b l a s t o m a t h a t p r e s e n t e d i n i t i a l l y as a n i n t r a e r a n i a l mass a n d was f u r t h e r c h a r a c t e r i z e d u l t r a s t r u c t u r a l l y b y t h e presence of n u m e r o u s d y s t r o p h i c axons. Case Report This 31 y e a r - o l d b l a c k w o m a n e n t e r e d t h e U n i v e r s i t y of T e x a s Medical B r a n c h H o s p i t a l 6 weeks a f t e r t h e o n s e t of n u m b n e s s o f her left cheek. This s y m p t o m p r o g r e s s e d slowly to i n v o l v e t h e lower p o r t i o n of t h e left side of her face a n d t h e r o o f o f h e r m o u t h . I t was a c c o m p a n i e d b y a n o n p a i n f u l s e n s a t i o n of fullness in h e r left ear. 13 Acta neuroi)ath. (Berl.) Bd. 31
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Physical examination revealed a diminished corneal reflex and hypesthesia in the distribution of the second and third divisions of the left trigeminal nerve. There was bitemporal hemianopsia but auditory acuity and olfaction were normal. Roentgenograms of the skull showed a midline and right parasellar mass with mottled calcifications t h a t extended into the sphenoid sinus. A radioisotopic brain scan revealed a large area of uptake in the midline and to the left of the sella. Carotid and vertebral angiography further delineated a large midline mass with extensions into both middle fossae and the sphenoid sinus. The cavernous and meningohypophyseal branches of the internal carotid arteries were increased in prominence. The proximal right middle cerebral artery was elevated and the right vein of Rosenthal was elevated and displaced posteriorly. The basilar artery and the pontomesencephalic vein were in their normal positions. Extensive preoperative laboratory studies including urinary hydroxy- and ketosteroids and serum cortisol, thyroxine, triiodothyronine and growth hormone levels were normal. A left frontotemporal craniotomy was performed and revealed an extremely vascular encapsulated neoplasm. Tumor was encountered between the two optic nerves and lateral to the left optic nerve and carotid artery. The left oculomotor nerve was involved by the lateral extension of the neoplasm. Partial intracapsular resections of the parasellar and left middle fossa components were performed. Post-operatively a urinary vanillylmandelic acid assay was within normal limits (3.1 nag per 24 hrs). The patient was given 4000 rads of radiation therapy and was alive and active with no progression of her disease 12 months later. The bitemporal hemianopsia and a postoperative left oculomotor palsy have improved. Materials and Methods For light microscopy, tissue was embedded in paraffin and the sections were stained with hematoxylin-eosin, trichrome, phosphotungstic acid--hematoxylin and Bodian silver techniques. For electron microscopy, tissue fragments were fixed in 0.1 M caeody]atebuffered 4 ~ glutaraldehyde. The small blocks were post-fixed in 0.1 M cacodylate buffered 1 ~ osmium tetroxide, dehydrated in alcohol and embedded in Araldite epoxy resin. Sections, 2 ~ thick, were cut with glass knives, stained with alkaline toluidine blue and examined by light microscopy in order to select suitable blocks. Thin sections were cut with diamond knives and stained with uranyl acetate and lead citrate prior to examination in ~ Philips EM201 electron microscope. Results Light Microscopy The neoplasm was highly cellular and consisted of sheets and nests of cells separated by a finely fibrillary stroma (Fig. la). The individual cells had round to fusiform nuclei surrounded b y scanty perinuclear cytoplasm. I n a few areas cells were clustered about anuclear loci forming abortive H o m e r Wright rosettes (Fig. l b). 2~o perivascular rosettes or true neuroepithelial rosettes with patent lumens were evident. Mitoses were relatively sparse. Bodian silver and phosphotungstic acid--hematoxylin stains failed to demonstrate neurites or glial processes respectively. Blood vessels and fibrous tissue trabecnlae were not especially
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Fig. 1. (a) Light micrograph showing that the neoplasm consisted predominantly of sheets and nests of cells with a fibrill~ry stroma. ( • 145). (b) Higher magnification of one of the rare Homer Wright pseudorosettes. ( • 520) Fig. 2. Electron micrograph showing one of the neoplastic neurons. Note the dense cored vesicles scattered widely throughout the cytoplasm. (• 7900) 13"
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conspicuous. A few loci of fresh operative hemorrhage were present. Only small foci of mineralization were present in the surgical specimen despite its prominence on X-rays. Light microscopy of the 2 ~z epoxy sections demonstrated nucleoli and perinuclear cytoplasm more clearly than was evident from the paraffin sections. Even in retrospect, after the ultrastructural features were known, dystrophic axons could not be recognized by light microscopy. Electron Microscopy
The predominant cell type appeared to be immature neoplastic neurons (Fig. 2). The nuclei were rslatively large and round to oval. Folds and indentations in the nuclear membrane were infrequently encountered. The cytoplasm ranged from abundant to sparse. Cisterns of rough endoplasmic reticulum and ribosomal rosettes were present. The Golgi apparatus was often prominent. The mitochondria were numerous and occasionally showed mild artifactual distension. Variable numbers of microtubules (240 A) and neurofilaments (100 A) were present in the perikarya. A conspicuous feature of these cells was the presence of scattered densecored vesicles t h a t averaged 1200 A in diameter. The dense core was surrounded b y an electron lucent zone t h a t in turn, was surrounded by a unit membrane. Usually only a small number of the vesicles were present in the perikarya and they were widely scattered without particular relation to any of the other perikaryal organeltes. Dense bodies, ]ysosomes, lipofuscin granules and centrio]es were variably encountered. Rarely the neoplastic cells were clustered about an apparently e m p t y space forming a rosette (Fig. 3). The lumenal surface was studded with microvilli. These contained filamentous material but lacked the highly organized microtubular arrays found in cilia. The majority of the neoplastic neurons were surrounded by myriads of neurites and occasional axonal terminals (Fig.4). The neurites contained admixtures of microtubules and neurofilaments. Occasional axosomatic synapses could be identified b y their membrane specializations. Axonal hillocks could not be recognized. Clusters of neurites containing dense cored vesicles were also encountered away from the perikarya (Fig. 5). The most distinctive ultrastructural feature of this neoplasm was the presence of numerous dystrophic axons. These structures appeared as ovoid or fusiform enlargements along the course of or at the termination of neurites (Figs.6--8). Some were adjacent to the neuronal perikarya (Figs. 6 and 7) while others were accompanied by cell processes. The dystrophic axons contained an abundance of bizarre organelles. Regularly present were irregular tubules of variable diameter. In some of the dystrophic axons, the tubules were interconnected and formed a complex network. They were often accompanied by and occasionally connected with arrays of roughly parallel membranes. Clefts were sometimes found between parallel membranes. Variable numbers of dense bodies, bizarre mitochondria, dense cored vesicles, microtubules and neurofilaments were present in the dystrophic axons. Some of the dystrophic axons formed synapses onto the neoplastic neurons (Fig. 7).
Fig. 3. Elec~ron micrograph showing a rosette. The lumenal surface is studded with microvilli. ( X 19500) Fig. 4. Higher magnification electron micrograph showing a portion of one of ~he neoplastic neurons surrounded b y neurites a n d a n axosomatic synapse. ( X 39 000)
186
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Fig.5. Electron micrograph showing a cluster of nenrites containing dense cored vesicles. (• ~5600) Fig. 6. Electron micrograph showing ~ dystrophic ~xon adjacent to the perikaryon of a neoplastic neuron. ( X 13600)
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Fig. 7. Higher magnification electron micrograph showing a synapse between a dystrophic axon and the perikaryon of a neoplastic neuron. (X 29000) Fig. 8. Electron micrograph showing a dystrophic ~xon remote from neuronal perikary~. The adjacent profile of Schwann cell cytoplasma is surrounded by a conspicuous basement membrane and is indented by multiple neurites. (• 13500)
188
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Profiles of cytoplasm, presumed to be Schwann cell cytoplasm, were rarely encountered (Fig. 8) but when seen, were surrounded b y a conspicuous basement and were deeply indented b y a variable number of neuritcs.
Discussion Esthesioneuroblastomas or olfactory neuroblastomas are well known but relatively rare neurogcnic tumors. The lesion was probably first described b y Berger et al. in 1924. These authors reported a neurogenic neoplasm t h a t contained true ncuroepithelial rosettes. They designated the lesion as an olfactory esthesioneuroepithelioma. Two years later Berger and Coutard described a similar neurogenie neoplasm t h a t lacked the true neuroepithelial rosettes. For this tumor the authors employed the t e r m olfactory esthesioneurocytoma. Other French authors (Gricouroff and Dulac; P o r t m a n n and Beillard; Terracol et al.) reported similar tumors with pseudoroscttes t h a t they regarded as sympathetic in nature. Many recent authors such as Obert et al., Hamilton et al. and K a h n employ esthesioneuroblastoma or olfactory ncuroblastoma as a generic t e r m for all of these variants. The exact site of origin of the esthcsioneuroblastoma is controversial. The majority of writers assume an origin from olfactory receptor cells. However a number of other structures in and about the nasal cavity have been proposed b y various authors over the years (Hamilton et al.). These arguments are of little significance if the neoplasms arise from derivatives of the cranial neural crest in which case they can be regarded simply as cranial neurocristopathies analogous to extracranial neuroblastomas (Bolande). This concept would also accomodate a spectrum of lesions with varying degrees of differentiation. An increasing number of esthesioneuroblastomas, like the present example, have been reported as initially manifesting themselves within the cranial cavity (Hamilton et al.). These eases introduce the additional diagnostic problem of distinguishing them from the cerebral neuroblastomas. However the cerebral ncuroblastomas are intraccrcbral tumors rather than merely intracranial lesions and all have appeared in individuals less than 10 years of age (Rubinstein). Extracranial neuroblastomas are notorious for their widespread metastases including involvement of the skull. I n the present cases this possibility seems to be satisfactorily excluded by the relatively long post-operative course during which time no evidence of any extraeranial neoplasm has been uncovered. Furthermore, unlike the present case, the majority of patients with extracranial neuroblastomas have elevated vanillylmandelic acid levels (Gitlow et al.). To date, only two other examples of esthesioneuroblastomas have been described nltrastructurally. McGavran published a brief account in which he emphasized the presence of biogenic amine granules. More recently K a h n has emphasized the presence of neuritic processes and neurosecretory granules similar to those in adrenal neuroblastomas. I n addition to these features, our specimen was also characterized b y the presence of numerous dystrophic axons. These distinctive axonal enlargements filled with bizarre cytoplasmic organelles are often regarded as a manifestation of chronic neuronal injury and have been observed in a wide variety of conditions (Jellinger). I t is of special interest t h a t
Intracr~nial Esthesioneuroblastoma
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such s t r u c t u r e s have been described a n d i l l u s t r a t e d p r e v i o u s l y i n a ganglioneurob l a s t o m a (Staley et al.) a l t h o u g h t h e y were n o t d e s i g n a t e d as dystrophic axons. References Berger, L., Coutard, H. : L'esth~sioneurocytome olfactif. Bull. Ass. fran~. Cancer 15, 404--414 (1926) Berger, L., Luc, R. : L'esth4sioneuro~pith61iome olfactif. Bull. Ass. fran 9. Cancer 13, 410--421 (1924). Bolande, R. P. : The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopments. Human Path. 5, 409--429 (1974) Castro, L., de la Pava, S., Webster, J. H. : Esthesioneuroblastomas--a report of 7 cases. Amer. J. Boentgenol. 105, 7--13 (1969) Fitz-Hugh, G.S., Allen, M.S., Rucker, T.N., Sprinkle, P. M. : Olfactory neuroblastoma (esthesioneuroblastoma). Arch. Otolaryng. 81, 161--168 (1965) Gitlow, S. E., Dziedzic, L. B., Strauss, L., Greenwood, S. M., Dziedzic, S.W.: Biochemical and histologie determinants in the prognosis of neuroblastoma. Cancer 82, 898--905 (1973) Gricouroff, G., Dulac, G. : Neuroblastome des fosses nasales. Ann. Otol. (St. Louis) 60, 77--83 (1943) Hamilton, A. E., Rubinstein, L. J., Poole, G. J. : Primary intracranial esthesioneuroblastoma (olfactory neuroblastoma). J. Neurosurg. 38, 548 556 (1973) Jellinger, K. : Neuroaxonal dystrophy: Its natural history and related disorders. In: Progress in neuropathology. H.M. Zimmerman (ed.), Vol. 2, pp. 129--180. New York-London: Grune and Stratton 1972 Kahn, L. B. : Esthesioneuroblastoma: a light and electron microscopic study. Human Path. 5, 364--371 (1974) Lewis, J. S., Hutter, I~. V. P., Tollefsen, H. R., Foote, F. W., Jr. : Nasal tumors of olfactory origin. Arch. Otolaryng. 81, 169--174 (1965) McG~vran, M. H.: Neurogenous nasal neoplasms. Ann. Otol. (St. Louis) 79, 547--550 (1970) Obert, G. J., Devine, K. D., McDonald, J. R. : Olfactory neuroblastomas. Cancer 13, 205--215 (1960) Portmann, G., Beillard, P.-F.: Les tumcurs nerveuses des fosses nasales. Rev. Lyrang. (Bordeaux) 68, 1--54, 125--144 (1947) I~ubinstein, L. J. : Cytogenesis and differentiation of primitive central neuroepithelial tumors. J. Neuropath. exp. Neurol. 31, 7--26 (1972) Staley, N. A., Polesky, H. F., Bensch, K. G. : Fine structural and biochemical studies on the malignant ganglioneuroma. J. Neuropath. exp. Neurol. 26, 634--653 (1967) Terracol, J., Guerrier, Y., Barjon, P.: Un cas de tumeur nerveuse rare des fosses nasales: sympathome sympathogonique. Rev. Laryng. (Bordeaux) 72, 603--606 (1951) Sydney S. Schochet, Jr., M.D. Division of Neuropathology Department of Pathology University of Texas Medical Branch Galveston, Texas 77550: U.S.A.
9 Original
Investigations
9 Travaux
originaux
Intracranial Esthesioneuroblastoma A L i g h t and Electron M i c r o s c o p i c S t u d y S y d n e y S. Schochet, Jr., B r u c e Peters, J o h n O'Neal, a n d W i l l i a m F. McCormick Division of Neuropathology, Department of Pathology, Department of Neurology and Division of Neurosurgcry, Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77550 Received August 29, 1974; Accepted December 18, 1974
Summary. A 31 year-old black woman with unilateral facial dysesthesia was found to have an intracranial parasellar mass that extended into the sphenoid sinus. By light microscopy, the neoplasm appeared as nests of poorly differentiated neuroblasts in a finely fihrillary stroma and was diagnosed as an esthesioneuroblastoma. Electron microscopy confirmed the neuroblastic nature of the tumor with demonstration of neurites containing neurofilaments and neurotubnles, synapses and dense cored biogenic amine granules in perikarya and processes. This neoplasm was further characterized by the presence of numerous dystrophic axons that were evident only by electron microscopy. Key words: Esthesioncuroblastoma -- Neuroblastoma -- Biogenic Amine Granules -Dystrophic Axons.
Introduction E s t h e s i o n e u r o b l a s t o m a s are well k n o w n b u t r e l a t i v e l y rare neurogenic t u m o r s t h a t u s u a l l y arise in t h e n a s a l c a v i t y a n d p r e s e n t clinically with nasal o b s t r u c t i o n a n d epistaxis ( F i t z - H u g h et al. ; Lewis et al. ; Castro et al.). A few cases h a v e been r e p o r t e d in w h o m t h e t u m o r was m a n i f e s t e d i n i t a l l y as a n i n t r a c r a n i a l mass ( H a m i l t o n et al.). The i n t r a c r a n i a l t u m o r s are histologically i d e n t i c a l to t h e m o r e usual e s t h e s i o n e u r o b l a s t o m a s from t h e n a s a l cavities. B o t h t y p e s m u s t be distinguished from m e t a s t a t i c n e u r o b l a s t o m a s from e x t r a c r a n i a l sites a n d from t h e so-called p r i m a r y cerebral n e u r o b l a s t o m a s . W e arc a w a r e of o n l y two r e p o r t s describing t h e u l t r a s t r u c t u r e of e s t h e s i o n e u r o b l a s t o m a s , b o t h b a s e d on specimens f r o m t h e n a s a l cavities ( M c G a v r a n ; K a h n ) . The p r e s e n t r e p o r t describes t h e e l e c t r o n microscopic findings in a n esthesion e u r o b l a s t o m a t h a t p r e s e n t e d i n i t i a l l y as a n i n t r a e r a n i a l mass a n d was f u r t h e r c h a r a c t e r i z e d u l t r a s t r u c t u r a l l y b y t h e presence of n u m e r o u s d y s t r o p h i c axons. Case Report This 31 y e a r - o l d b l a c k w o m a n e n t e r e d t h e U n i v e r s i t y of T e x a s Medical B r a n c h H o s p i t a l 6 weeks a f t e r t h e o n s e t of n u m b n e s s o f her left cheek. This s y m p t o m p r o g r e s s e d slowly to i n v o l v e t h e lower p o r t i o n of t h e left side of her face a n d t h e r o o f o f h e r m o u t h . I t was a c c o m p a n i e d b y a n o n p a i n f u l s e n s a t i o n of fullness in h e r left ear. 13 Acta neuroi)ath. (Berl.) Bd. 31
182
S.S. Schochet, Jr., et al.
Physical examination revealed a diminished corneal reflex and hypesthesia in the distribution of the second and third divisions of the left trigeminal nerve. There was bitemporal hemianopsia but auditory acuity and olfaction were normal. Roentgenograms of the skull showed a midline and right parasellar mass with mottled calcifications t h a t extended into the sphenoid sinus. A radioisotopic brain scan revealed a large area of uptake in the midline and to the left of the sella. Carotid and vertebral angiography further delineated a large midline mass with extensions into both middle fossae and the sphenoid sinus. The cavernous and meningohypophyseal branches of the internal carotid arteries were increased in prominence. The proximal right middle cerebral artery was elevated and the right vein of Rosenthal was elevated and displaced posteriorly. The basilar artery and the pontomesencephalic vein were in their normal positions. Extensive preoperative laboratory studies including urinary hydroxy- and ketosteroids and serum cortisol, thyroxine, triiodothyronine and growth hormone levels were normal. A left frontotemporal craniotomy was performed and revealed an extremely vascular encapsulated neoplasm. Tumor was encountered between the two optic nerves and lateral to the left optic nerve and carotid artery. The left oculomotor nerve was involved by the lateral extension of the neoplasm. Partial intracapsular resections of the parasellar and left middle fossa components were performed. Post-operatively a urinary vanillylmandelic acid assay was within normal limits (3.1 nag per 24 hrs). The patient was given 4000 rads of radiation therapy and was alive and active with no progression of her disease 12 months later. The bitemporal hemianopsia and a postoperative left oculomotor palsy have improved. Materials and Methods For light microscopy, tissue was embedded in paraffin and the sections were stained with hematoxylin-eosin, trichrome, phosphotungstic acid--hematoxylin and Bodian silver techniques. For electron microscopy, tissue fragments were fixed in 0.1 M caeody]atebuffered 4 ~ glutaraldehyde. The small blocks were post-fixed in 0.1 M cacodylate buffered 1 ~ osmium tetroxide, dehydrated in alcohol and embedded in Araldite epoxy resin. Sections, 2 ~ thick, were cut with glass knives, stained with alkaline toluidine blue and examined by light microscopy in order to select suitable blocks. Thin sections were cut with diamond knives and stained with uranyl acetate and lead citrate prior to examination in ~ Philips EM201 electron microscope. Results Light Microscopy The neoplasm was highly cellular and consisted of sheets and nests of cells separated by a finely fibrillary stroma (Fig. la). The individual cells had round to fusiform nuclei surrounded b y scanty perinuclear cytoplasm. I n a few areas cells were clustered about anuclear loci forming abortive H o m e r Wright rosettes (Fig. l b). 2~o perivascular rosettes or true neuroepithelial rosettes with patent lumens were evident. Mitoses were relatively sparse. Bodian silver and phosphotungstic acid--hematoxylin stains failed to demonstrate neurites or glial processes respectively. Blood vessels and fibrous tissue trabecnlae were not especially
Intracrani~l Esthesioneuroblastom~
183
Fig. 1. (a) Light micrograph showing that the neoplasm consisted predominantly of sheets and nests of cells with a fibrill~ry stroma. ( • 145). (b) Higher magnification of one of the rare Homer Wright pseudorosettes. ( • 520) Fig. 2. Electron micrograph showing one of the neoplastic neurons. Note the dense cored vesicles scattered widely throughout the cytoplasm. (• 7900) 13"
184
S.S. Schochet, Jr., et al.
conspicuous. A few loci of fresh operative hemorrhage were present. Only small foci of mineralization were present in the surgical specimen despite its prominence on X-rays. Light microscopy of the 2 ~z epoxy sections demonstrated nucleoli and perinuclear cytoplasm more clearly than was evident from the paraffin sections. Even in retrospect, after the ultrastructural features were known, dystrophic axons could not be recognized by light microscopy. Electron Microscopy
The predominant cell type appeared to be immature neoplastic neurons (Fig. 2). The nuclei were rslatively large and round to oval. Folds and indentations in the nuclear membrane were infrequently encountered. The cytoplasm ranged from abundant to sparse. Cisterns of rough endoplasmic reticulum and ribosomal rosettes were present. The Golgi apparatus was often prominent. The mitochondria were numerous and occasionally showed mild artifactual distension. Variable numbers of microtubules (240 A) and neurofilaments (100 A) were present in the perikarya. A conspicuous feature of these cells was the presence of scattered densecored vesicles t h a t averaged 1200 A in diameter. The dense core was surrounded b y an electron lucent zone t h a t in turn, was surrounded by a unit membrane. Usually only a small number of the vesicles were present in the perikarya and they were widely scattered without particular relation to any of the other perikaryal organeltes. Dense bodies, ]ysosomes, lipofuscin granules and centrio]es were variably encountered. Rarely the neoplastic cells were clustered about an apparently e m p t y space forming a rosette (Fig. 3). The lumenal surface was studded with microvilli. These contained filamentous material but lacked the highly organized microtubular arrays found in cilia. The majority of the neoplastic neurons were surrounded by myriads of neurites and occasional axonal terminals (Fig.4). The neurites contained admixtures of microtubules and neurofilaments. Occasional axosomatic synapses could be identified b y their membrane specializations. Axonal hillocks could not be recognized. Clusters of neurites containing dense cored vesicles were also encountered away from the perikarya (Fig. 5). The most distinctive ultrastructural feature of this neoplasm was the presence of numerous dystrophic axons. These structures appeared as ovoid or fusiform enlargements along the course of or at the termination of neurites (Figs.6--8). Some were adjacent to the neuronal perikarya (Figs. 6 and 7) while others were accompanied by cell processes. The dystrophic axons contained an abundance of bizarre organelles. Regularly present were irregular tubules of variable diameter. In some of the dystrophic axons, the tubules were interconnected and formed a complex network. They were often accompanied by and occasionally connected with arrays of roughly parallel membranes. Clefts were sometimes found between parallel membranes. Variable numbers of dense bodies, bizarre mitochondria, dense cored vesicles, microtubules and neurofilaments were present in the dystrophic axons. Some of the dystrophic axons formed synapses onto the neoplastic neurons (Fig. 7).
Fig. 3. Elec~ron micrograph showing a rosette. The lumenal surface is studded with microvilli. ( X 19500) Fig. 4. Higher magnification electron micrograph showing a portion of one of ~he neoplastic neurons surrounded b y neurites a n d a n axosomatic synapse. ( X 39 000)
186
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Fig.5. Electron micrograph showing a cluster of nenrites containing dense cored vesicles. (• ~5600) Fig. 6. Electron micrograph showing ~ dystrophic ~xon adjacent to the perikaryon of a neoplastic neuron. ( X 13600)
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Fig. 7. Higher magnification electron micrograph showing a synapse between a dystrophic axon and the perikaryon of a neoplastic neuron. (X 29000) Fig. 8. Electron micrograph showing a dystrophic ~xon remote from neuronal perikary~. The adjacent profile of Schwann cell cytoplasma is surrounded by a conspicuous basement membrane and is indented by multiple neurites. (• 13500)
188
S.S. Schoche$, Jr., et al.
Profiles of cytoplasm, presumed to be Schwann cell cytoplasm, were rarely encountered (Fig. 8) but when seen, were surrounded b y a conspicuous basement and were deeply indented b y a variable number of neuritcs.
Discussion Esthesioneuroblastomas or olfactory neuroblastomas are well known but relatively rare neurogcnic tumors. The lesion was probably first described b y Berger et al. in 1924. These authors reported a neurogenic neoplasm t h a t contained true ncuroepithelial rosettes. They designated the lesion as an olfactory esthesioneuroepithelioma. Two years later Berger and Coutard described a similar neurogenie neoplasm t h a t lacked the true neuroepithelial rosettes. For this tumor the authors employed the t e r m olfactory esthesioneurocytoma. Other French authors (Gricouroff and Dulac; P o r t m a n n and Beillard; Terracol et al.) reported similar tumors with pseudoroscttes t h a t they regarded as sympathetic in nature. Many recent authors such as Obert et al., Hamilton et al. and K a h n employ esthesioneuroblastoma or olfactory ncuroblastoma as a generic t e r m for all of these variants. The exact site of origin of the esthcsioneuroblastoma is controversial. The majority of writers assume an origin from olfactory receptor cells. However a number of other structures in and about the nasal cavity have been proposed b y various authors over the years (Hamilton et al.). These arguments are of little significance if the neoplasms arise from derivatives of the cranial neural crest in which case they can be regarded simply as cranial neurocristopathies analogous to extracranial neuroblastomas (Bolande). This concept would also accomodate a spectrum of lesions with varying degrees of differentiation. An increasing number of esthesioneuroblastomas, like the present example, have been reported as initially manifesting themselves within the cranial cavity (Hamilton et al.). These eases introduce the additional diagnostic problem of distinguishing them from the cerebral neuroblastomas. However the cerebral ncuroblastomas are intraccrcbral tumors rather than merely intracranial lesions and all have appeared in individuals less than 10 years of age (Rubinstein). Extracranial neuroblastomas are notorious for their widespread metastases including involvement of the skull. I n the present cases this possibility seems to be satisfactorily excluded by the relatively long post-operative course during which time no evidence of any extraeranial neoplasm has been uncovered. Furthermore, unlike the present case, the majority of patients with extracranial neuroblastomas have elevated vanillylmandelic acid levels (Gitlow et al.). To date, only two other examples of esthesioneuroblastomas have been described nltrastructurally. McGavran published a brief account in which he emphasized the presence of biogenic amine granules. More recently K a h n has emphasized the presence of neuritic processes and neurosecretory granules similar to those in adrenal neuroblastomas. I n addition to these features, our specimen was also characterized b y the presence of numerous dystrophic axons. These distinctive axonal enlargements filled with bizarre cytoplasmic organelles are often regarded as a manifestation of chronic neuronal injury and have been observed in a wide variety of conditions (Jellinger). I t is of special interest t h a t
Intracr~nial Esthesioneuroblastoma
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such s t r u c t u r e s have been described a n d i l l u s t r a t e d p r e v i o u s l y i n a ganglioneurob l a s t o m a (Staley et al.) a l t h o u g h t h e y were n o t d e s i g n a t e d as dystrophic axons. References Berger, L., Coutard, H. : L'esth~sioneurocytome olfactif. Bull. Ass. fran~. Cancer 15, 404--414 (1926) Berger, L., Luc, R. : L'esth4sioneuro~pith61iome olfactif. Bull. Ass. fran 9. Cancer 13, 410--421 (1924). Bolande, R. P. : The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopments. Human Path. 5, 409--429 (1974) Castro, L., de la Pava, S., Webster, J. H. : Esthesioneuroblastomas--a report of 7 cases. Amer. J. Boentgenol. 105, 7--13 (1969) Fitz-Hugh, G.S., Allen, M.S., Rucker, T.N., Sprinkle, P. M. : Olfactory neuroblastoma (esthesioneuroblastoma). Arch. Otolaryng. 81, 161--168 (1965) Gitlow, S. E., Dziedzic, L. B., Strauss, L., Greenwood, S. M., Dziedzic, S.W.: Biochemical and histologie determinants in the prognosis of neuroblastoma. Cancer 82, 898--905 (1973) Gricouroff, G., Dulac, G. : Neuroblastome des fosses nasales. Ann. Otol. (St. Louis) 60, 77--83 (1943) Hamilton, A. E., Rubinstein, L. J., Poole, G. J. : Primary intracranial esthesioneuroblastoma (olfactory neuroblastoma). J. Neurosurg. 38, 548 556 (1973) Jellinger, K. : Neuroaxonal dystrophy: Its natural history and related disorders. In: Progress in neuropathology. H.M. Zimmerman (ed.), Vol. 2, pp. 129--180. New York-London: Grune and Stratton 1972 Kahn, L. B. : Esthesioneuroblastoma: a light and electron microscopic study. Human Path. 5, 364--371 (1974) Lewis, J. S., Hutter, I~. V. P., Tollefsen, H. R., Foote, F. W., Jr. : Nasal tumors of olfactory origin. Arch. Otolaryng. 81, 169--174 (1965) McG~vran, M. H.: Neurogenous nasal neoplasms. Ann. Otol. (St. Louis) 79, 547--550 (1970) Obert, G. J., Devine, K. D., McDonald, J. R. : Olfactory neuroblastomas. Cancer 13, 205--215 (1960) Portmann, G., Beillard, P.-F.: Les tumcurs nerveuses des fosses nasales. Rev. Lyrang. (Bordeaux) 68, 1--54, 125--144 (1947) I~ubinstein, L. J. : Cytogenesis and differentiation of primitive central neuroepithelial tumors. J. Neuropath. exp. Neurol. 31, 7--26 (1972) Staley, N. A., Polesky, H. F., Bensch, K. G. : Fine structural and biochemical studies on the malignant ganglioneuroma. J. Neuropath. exp. Neurol. 26, 634--653 (1967) Terracol, J., Guerrier, Y., Barjon, P.: Un cas de tumeur nerveuse rare des fosses nasales: sympathome sympathogonique. Rev. Laryng. (Bordeaux) 72, 603--606 (1951) Sydney S. Schochet, Jr., M.D. Division of Neuropathology Department of Pathology University of Texas Medical Branch Galveston, Texas 77550: U.S.A.
