Journal of Neuro-Oncology 9: 231-238, 1990. © 1990 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Central nervous system neurocytoma and neuroblastoma in adults-report of eight cases*
David N. Louis, Brooke Swearingen 1, Rita M. Linggood2, G. Richard Dickersin, Cynthia Kretschmar 3, Atul K. Bhan and E. Tessa Hedley-Whyte
Departments of Pathology, 1Neurosurgery, 2Radiation Medicine, and 3Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Key words: neuroblastoma, neurocytoma, central nervous system tumors, spinal cord tumor Summary The clinical features, pathologic findings and treatment courses of eight adults with central nervous system small-cell neuronal tumors were reviewed. Five patients had central neurocytomas, two patients central nervous system neuroblastomas, and one patient a neurocytoma-like spinal cord tumor. The neurocytomas were intraventricular, moderately cellular tumors with bland nuclei and perinuclear halos. Patients with neurocytoma were treated with surgery, radiation therapy, and/or chemotherapy, and have followed favorable clinical courses. The neuroblastomas were intraparenchymal, hypercellular tumors with necrosis and frequent mitoses. Patients with neuroblastomas were treated with surgery, radiation therapy and chemotherapy, with some clinical response, but overall poor survival. One of the two patients developed extracranial metastasis. The spinal cord tumor had histologic features of neurocytoma, and responded well to biopsy and radiation therapy. The cases are compared with the varieties of small-celled neuronal tumors described in the literature, and pathologic, histogenetic and treatment implications are discussed.
Introduction
Materials and methods
Central nervous system (CNS) tumors of neuronal origin are a morphologically and clinically heterogeneous group of neoplasms. Those neuronal tumors characterized by small cells - as opposed to the large-cell or ganglion cell tumors- can be divided into the neuroblastomas and neurocytomas. CNS neuroblastomas and neurocytomas are different with respect to age of occurence, site, prognosis, and response to therapy. We present five cases of central neurocytoma, two cases of CNS neuroblastoma, and one case of a spinal cord neurocytoma-like tumor, to highlight differences in histopathology, biology and prognosis.
Eight adult patients with small-celled neuronal tumors of the CNS were seen at the MGH between 1979 and 1989. Tumor samples obtained at surgery were fixed in formalin and embedded in paraffin. Routine hematoxylin and eosin stained slides were prepared in all cases, and selected cases were studied with Bodian's silver impregnation. Tissue was available in three cases for immunohistochemical analysis of formalin-fixed, paraffinembedded material, using the avidin-biotin complex method (Vector Laboratories). Polyclonal rabbit antisera to neuron-specific enolase (NSE) (Dako Co.) and monoclonal antibodies to glial fi-
* This paper was presented in part at the United States and Canadian Academy of Pathology meeting, Boston, MA, March 7, 1990
232 briUary acidic protein (GFAP) (LabSystems Inc.) and neurofilament protein (Dako Co. and BioGenex Lab.), were applied to all three cases, and monoclonal antibodies to synaptophysin and chromogranin (Boehringer Mannheim) to one. In five cases, tissue for electron microscopy was fixed in half-strength Karnovsky's solution, postfixed in osmium tetroxide, stained with uranyl acetate en bloc, dehydrated in graded ethanols, infiltrated with propylene oxide/Epon and embedded in Epon. One micron thick sections were correlated with the paraffin sections. Ultra-thin sections were made, stained with lead citrate and examined with a Philips 301 electron microscope. Cases were diagnosed as neurocytoma if they were intraventricular and had a predominantly clear-cell pattern, with Homer Wright rosette formation or ultrastructural evidence of tumor cell processes with micr0tubules, dense-core granules
and/or synaptic vesicles. Tumors were included as neuroblastoma when light microscopic examination revealed a hypercellular, small cell tumor with prominent Homer Wright rosettes, ganglion cells and/or positive Bodian silver impregnation, or when ultrastructural examination showed features as described above. Ganglion cell tumors and cases of'primitive neuroectodermal tumor' without clear evidence of neuroblastic differentiation were excluded.
Results
The clinical features of the eight patients are presented in Table 1. The patients' ages ranged from 16 to 67 years. Five of the eight were intraventricular tumors, and presented with headaches and signs of elevated intracranial pressure. Two tumors
Table 1. Clinical data Case/Age
Age/Gender Presentation
Tumor site
Surgery and subsequent treatment
Follow up
1. C.D.
47 yo M
seizures, left hemiparesis
right frontal lobe
2. R.B.
40 yo M
64yo F
1. unknown 2. left temporal lobe 3. T l l spine third and left lateral ventricle
died of prostatic ca 12 mos. died of tumor 42 mos.
3. Y.M.
1. 3yrs. seizures 2. aphasia/right arm weakness 3. flank pain 6 mos. memory loss personality change
4. M.R.
17 yo M
headache, vomiting
right lateral ventricle
5. D.D.
26 yo F
headaches
third and left lateral ventricle
6. K.H.
22yo F
headaches, vomiting
right lateral ventricle
7. R.G.
36 yo M
dizziness
8. N.F.
68 yo M
1.5 yr. left arm weakness
right lateral ventricle cervical cord
subtotal resection XRT: 60 Gy to tumor CCNU 1. XRT (outside hosp.) 2. subtotal resection intraarterial BCNU X4 3. spinal XRT subtotal resection VP shunt XRT: 52.5 Gy to tumor subtotal resection VP shunt chemotx: cytoxan/cisplatin XRT: 54 Gy to tumor, 30 Gy to axis subtotal resection VP shunt chemotx: cytoxan/cisplatin XRT: 54 Gy to tumor, 30 Gy to axis near total resection VP shunt XRT: 54Gy to tumor, 30Gy to axis near total resection biopsy XRT: 43.2 Gy to tumor
A/W 54 mos.
A/W 78 mos. A/W 14 mos.
A/W 11 mos.
A/W 58 mos. A/W 11 m o s .
VP = ventriculoperitoneal; XRT = irradiation therapy; A/W = alive and well.
233
Fig. 1. N e u r o b l a s t o m a : h y p e r c e l l u l a r i n t r a p a r e n c h y m a l t u m o r c o m p o s e d o f s m a l l ceils w i t h h y p e r c h r o m a t i c n u c l e i a n d scant c y t o p l a s m , w i t h s c a t t e r e d p y k n o t i c nuclei. C a s e 2, H a n d E , 425 x .
Fig. 2. N e u r o c y t o m a : m o d e r a t e l y cellular i n t r a v e n t r i c u l a r tum o r c o m p o s e d of cells w i t h u n i f o r m , b l a n d nuclei, p e r i n u c l e a r halos, a n d d e l i c a t e n e u r o f i b r i l l a r y b a c k g r o u n d w i t h a n u c l e a r zones. C a s e 3, H a n d E , 266 x .
were intraparenchymal brain lesions and one was an intramedullary spinal cord lesion; these presented with localizing findings. The pathological data are summarized in Table 2. Cases 1 and 2 were intraparenchymal lesions with necrosis, pyknotic nuclei, and frequent mitotic figures, and were classified as cerebral neuroblastomas (Fig. 1). Cases 5, 6 and 7 were cytolog-
ically bland intraventricular tumors, with prominent clear cell areas and no necrosis or mitotic figures (Fig. 2). Areas of delicate neurofibrillary background with anuclear zones were focally prominent. These correspond to the neurocytomas reported in the literature. Cases 3 and 4 were also classified as intraventricular neurocytomas, but showed additional histologic features such as ne-
Table 2. P a t h o l o g i c a l d a t a Case/Dx
H W rosettes
Ganglion cells
Silver
Mitotic figures
Necrosis
Halos
EM
1. N e u r o b l a s t o m a 2. N e u r o b l a s t o m a
++ rare
-
focal -
++ ++
+ + ++
focal
* NRL
3. N e u r o c y t o m a 4. N e u r o c y t o m a
rare + +
-
* *
-
++ ++
++ focal
NRL NRL
5. N e u r o c y t o m a
++
.
focal
*
6. N e u r o c y t o m a 7. N e u r o c y t o m a
rare ++
-
focal ++
NRL *
.
. * *
. -
-
Immuno
+ + NSE - NF, GFAP + + NSE - NF, GFAP + + NSE - NF, GFAP, Syn, C h r o m
8. N e u r o c y t o m a
rare
rare
*
-
-
++
NRL
H W r o s e t t e s = H o m e r W r i g h t r o s e t t e s ; Silver = B o d i a n silver i m p r e g n a t i o n ; H a l o s = p e r i n u c l e a r h a l o s (clear cells); E M = e l e c t r o n m i c r o s c o p i c d a t a ; I m m u n o = i m m u n o h i s t o c h e m i c a l data;* = d a t a n o t a v a i l a b l e ; ( + + ) = p r e s e n t ; ( - ) = a b s e n t ; N R L = n e u r o n a l f e a t u r e s : cell p r o c e s s e s w i t h m i e r o t u b u l e s a n d d e n s e - c o r e g r a n u l e s ; N S E = n e u r o n - s p e c i f i c e n o l a s e ; N F = n e u r o f i l a m e n t p r o t e i n ; G F A P = glial fibrillary acidic p r o t e i n ; Syn = s y n a p t o p h y s i n ; C h r o m = c h r o m o g r a n i n .
234
Fig. 3. Neurocytoma: Homer Wright rosette areas in an intraventricular tumor. Rare cells in this field show perinuclear clearing (left center). Case 5, H and E, 670 x.
crosis, rare clear cell areas, and/or increased cellularity. Homer Wright rosettes were present in both the neuroblastomas and neurocytomas (Fig. 3). Case 8 histologically resembled a neurocytoma but was located in the spinal cord. Immunohistochemical studies showed all three tumors studied (cases 4, 5 and 7) to be NSE-positive and GFAP-negative. These tests were helpful in ruling out GFAP-positive tumors such as astrocytoma, subependymoma and ependymoma, but were not helpful in the differential diagnosis of oligodendroglioma. The positive NSE results did not aid in the diagnosis because of the lack of specificity of NSE staining. Monoclonal antibodies to synaptophysin and chromogranin failed to stain the one lesion studied. Electron microscopy showed cells with a high nuclear: cytoplasmic ratio, round nuclei with clumped chromatin, and rosette formation with central neurofibrillary cores (Fig. 4a). Cell processes contained microtubules and dense core granules in each case examined (cases 2, 3, 4, 6 and 8) (Fig. 4b). In case 3, synaptic vesicles were noted (Fig. 4c). In cases 3, 6 and 8, the light microscopy had suggested oligodendroglioma, but the electron microscopy findings were diagnostic of neuronal differentiation. No uniform therapeutic protocol was employed. All patients, except case 8, underwent a surgical
resection and radiation therapy. The intraparenchymal lesions (cases 1 and 2) received either BCNU or CCNU. Case 2 originally presented with an intraparenchymal temporal lobe lesion, and returned with systemic metastasis to the T l l vertebral body, which was treated with radiation therapy. Cases 3, 4, and 5 were treated with subtotal resection followed by radiation therapy. Cases 4 and 5 were treated with chemotherapy prior to irradiation. Near total resections were performed on cases 6 and 7, and the spinal cord lesion (case 8) was biopsied and irradiated. Most patients with intraventricular tumors were evaluated with myelography and then treated with craniospinal irradiation. Of the five patients with intraventricular tumors, three have been followed for 14 months or less, but are without clinical deficits at this time; the other two patients, including one tumor with necrosis, show no evidence of progression at 58 months and 78 months. Those patients with intraparenchymal lesions have fared less well: case i died after 1 year of metastatic prostate cancer, and case 2 died of recurrent neuroblastoma 42 months after diagnosis. The patient with the intramedullary cervical cord lesion has done well, with no progression at 54 months.
Discussion
Neuroblastomas are tumors composed of neuronal precursor cells [1-4]. These cells are often poorlydifferentiated and may show only a few neuronal features by electron microscopy [5-7]. Horten and Rubinstein's and Bennett and Rubinstein's seminal studies of cerebral neuroblastomas reported a group of CNS tumors which occurred primarily in children in the first decade of life and which resembled medulloblastoma by light microscopy [8, 9]. The tumors were predominantly intraparenchyreal lesions which followed aggressive courses, although occasional long survivals were noted. Subsequent reports have confirmed these characteristics, and have cited their uncommon occurence in adults [5-7, 10-12]. Reports of a wider spectrum of CNS small-cell
235
Fig. 4: Neurocytoma: 4a. Electron micrograph of Homer Wright rosette showing tumor cells with high nuclear: cytoplasmic ratio, round nuclei with clumped chromatin, and central neurofibrillary core of tumor cell processes. Case 4, 1600 x. 4b. Tumor cell processes containing microtubules and dense core granules. Case 6, 19350 x. 4c. Tumor cell processes with synaptic vesicles and microtubules. Case 3, 15570 ×.
236 neuronal tumors, however, have increased over the past ten years [5-7, 11-26]. From these cases, it is apparent that CNS neuronal tumors may assume a wider variety of forms than previously described, both clinically and pathologically. Hassoun et al. first documented two tumors which were neuroblastic by EM, but which resembled oligodendroglioma rather than medulloblastoma by light microscopy [16]. They termed this tumor 'central neurocytoma,' stressing both the relatively mature appearing neuronal population of the tumor cells and the relatively benign clinical course. Other authors have documented similar cases [7, 18-20, 24-26]. The neurocytomas, unlike most CNS neuroblastomas, occur predominantly in patients in the second and third decades of life and tend to be found in the lateral ventricles. These tumors follow more benign courses that the neuroblastomas, and may in some cases be cured by excision alone. Some papers have stated that the light microscopic picture of the central neurocytoma is nearly identical to that of oligodendroglioma [19, 24]. We would, however, stress the following differences: 1. The nuclei are more varied and euchromatic in the neurocytomas. 2. The fibrillary background is more extensive and more delicate in the neurocytomas, with anuclear zones. 3. The neurocytoma vasculature is delicate and usually inconspicuous, compared with the intricate, prominent branching pattern of the oligodendroglioma. Ultrastructurally, the neurocytoma contains well-differentiated cells [7, 16, 20, 24, 25] which resemble small neurons to the extent of sometimes showing synapse formation [7, 16, 25]. In a cytogenetic scheme, these tumors can be viewed in two ways: 1. The cells of neurocytoma could be neuronal cells intermediate between those immature cells of the neuroblastoma and those mature cells of the gangliocytoma. In this regard, maturing cortical neuroblasts in human fetal brain sometimes show distinct perinuclear halos, while the less mature germinal matrix cells do not. In addition, oligodendroglioma-like areas in medullo-
blastomas have recently been shown to be neuroblastic by immunohistochemical markers [27], and perhaps represent maturation toward a mature cerebellar granular cell. While the perinuclear halos are probably artefactual, they nonetheless may reflect a tendency for more mature neuroblasts to display perinuclear halos in formalin-fixed, paraffin-embedded material. . The cells of the neurocytoma may instead be mature cells which resemble small granular neurons rather than large pyramidal or ganglionic cells. The location of neurocytomas in the area of the fetal germinal matrix suggests that they may arise from residual, committed small neuronal cells remaining along the ventricular surface. In this regard, they are perhaps akin to the subependymal giant cell tumor associated with tuberous sclerosis or even the subependymoma - two other relatively benign ventricular wall tumors that seem to have arisen from the area of the original matrix. The spinal cord tumor appears to be the first neurocytoma to be reported outside of the intracranial ventricular system and could have arisen from cells adjacent to the central canal- an area like the supratentorial germinal matrix, in which neuronal precursor cells were present in fetal life. In summary, there exists a histologically and clinically heterogeneous group of small-celled neuronal CNS tumors. One group has suggested that these tumors might be graded, with grade 4 corresponding to a poorly-differentiated tumor such as a PNET with focal neuronal differentiation, and grade 1 corresponding to the so-called neurocytoma [7]. In such a system, our cases i and 2 would be grade 4, cases 3 and 4 would be intermediate grade primarily because of the necrosis, and cases 5, 6, 7, and perhaps 8 would be grade 1. Cases 3 and 4, however, have done as well clinically as the intraventricular tumors without necrosis. In fact, the location and lack of mitotic activity may be more important than the presence of necrosis or focal hypercellularity in predicting outcome. In addition, the different location and age predilection between neurocytomas and the typical CNS neuroblastoma of childhood suggests that placing such
238 ular neurocytoma: clinicopathological features of six cases. J Neurosurg 68: 665-670, 1988 25. Kubota T, Kawano H, Hayashi M. Cerebral neurocytornalight, electron microscopic and irnrnunohistochemical features (abstract). J Neuropath Exp Neurol 47: 376, 1988 26. Ferreol E, Sawaya R, de Courten-Myers GM. Primary cerebral neuroblastorna (neurocytoma) in adults. J NeuroOnc 7: 121-128, 1989 27. Katsetos CD, Herman MM, Frankfurter A, Gass P, Collins VP, Walker CC, Rosernberg S, Barnard RO, Rubinstein
LJ. Cerebellar desrnoplastic rnedulloblastorna - a further irnrnunohistochernical characterization of the reticulin-free islands. Arch Pathol Lab Med 113: 1019-1029, t989
Address for offprints: D.N. Louis, Dept of Pathology (Neuropathology), Warren 3, Massachusetts General Hospital, Boston, MA 02114, USA
Clinical Study
Central nervous system neurocytoma and neuroblastoma in adults-report of eight cases*
David N. Louis, Brooke Swearingen 1, Rita M. Linggood2, G. Richard Dickersin, Cynthia Kretschmar 3, Atul K. Bhan and E. Tessa Hedley-Whyte
Departments of Pathology, 1Neurosurgery, 2Radiation Medicine, and 3Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Key words: neuroblastoma, neurocytoma, central nervous system tumors, spinal cord tumor Summary The clinical features, pathologic findings and treatment courses of eight adults with central nervous system small-cell neuronal tumors were reviewed. Five patients had central neurocytomas, two patients central nervous system neuroblastomas, and one patient a neurocytoma-like spinal cord tumor. The neurocytomas were intraventricular, moderately cellular tumors with bland nuclei and perinuclear halos. Patients with neurocytoma were treated with surgery, radiation therapy, and/or chemotherapy, and have followed favorable clinical courses. The neuroblastomas were intraparenchymal, hypercellular tumors with necrosis and frequent mitoses. Patients with neuroblastomas were treated with surgery, radiation therapy and chemotherapy, with some clinical response, but overall poor survival. One of the two patients developed extracranial metastasis. The spinal cord tumor had histologic features of neurocytoma, and responded well to biopsy and radiation therapy. The cases are compared with the varieties of small-celled neuronal tumors described in the literature, and pathologic, histogenetic and treatment implications are discussed.
Introduction
Materials and methods
Central nervous system (CNS) tumors of neuronal origin are a morphologically and clinically heterogeneous group of neoplasms. Those neuronal tumors characterized by small cells - as opposed to the large-cell or ganglion cell tumors- can be divided into the neuroblastomas and neurocytomas. CNS neuroblastomas and neurocytomas are different with respect to age of occurence, site, prognosis, and response to therapy. We present five cases of central neurocytoma, two cases of CNS neuroblastoma, and one case of a spinal cord neurocytoma-like tumor, to highlight differences in histopathology, biology and prognosis.
Eight adult patients with small-celled neuronal tumors of the CNS were seen at the MGH between 1979 and 1989. Tumor samples obtained at surgery were fixed in formalin and embedded in paraffin. Routine hematoxylin and eosin stained slides were prepared in all cases, and selected cases were studied with Bodian's silver impregnation. Tissue was available in three cases for immunohistochemical analysis of formalin-fixed, paraffinembedded material, using the avidin-biotin complex method (Vector Laboratories). Polyclonal rabbit antisera to neuron-specific enolase (NSE) (Dako Co.) and monoclonal antibodies to glial fi-
* This paper was presented in part at the United States and Canadian Academy of Pathology meeting, Boston, MA, March 7, 1990
232 briUary acidic protein (GFAP) (LabSystems Inc.) and neurofilament protein (Dako Co. and BioGenex Lab.), were applied to all three cases, and monoclonal antibodies to synaptophysin and chromogranin (Boehringer Mannheim) to one. In five cases, tissue for electron microscopy was fixed in half-strength Karnovsky's solution, postfixed in osmium tetroxide, stained with uranyl acetate en bloc, dehydrated in graded ethanols, infiltrated with propylene oxide/Epon and embedded in Epon. One micron thick sections were correlated with the paraffin sections. Ultra-thin sections were made, stained with lead citrate and examined with a Philips 301 electron microscope. Cases were diagnosed as neurocytoma if they were intraventricular and had a predominantly clear-cell pattern, with Homer Wright rosette formation or ultrastructural evidence of tumor cell processes with micr0tubules, dense-core granules
and/or synaptic vesicles. Tumors were included as neuroblastoma when light microscopic examination revealed a hypercellular, small cell tumor with prominent Homer Wright rosettes, ganglion cells and/or positive Bodian silver impregnation, or when ultrastructural examination showed features as described above. Ganglion cell tumors and cases of'primitive neuroectodermal tumor' without clear evidence of neuroblastic differentiation were excluded.
Results
The clinical features of the eight patients are presented in Table 1. The patients' ages ranged from 16 to 67 years. Five of the eight were intraventricular tumors, and presented with headaches and signs of elevated intracranial pressure. Two tumors
Table 1. Clinical data Case/Age
Age/Gender Presentation
Tumor site
Surgery and subsequent treatment
Follow up
1. C.D.
47 yo M
seizures, left hemiparesis
right frontal lobe
2. R.B.
40 yo M
64yo F
1. unknown 2. left temporal lobe 3. T l l spine third and left lateral ventricle
died of prostatic ca 12 mos. died of tumor 42 mos.
3. Y.M.
1. 3yrs. seizures 2. aphasia/right arm weakness 3. flank pain 6 mos. memory loss personality change
4. M.R.
17 yo M
headache, vomiting
right lateral ventricle
5. D.D.
26 yo F
headaches
third and left lateral ventricle
6. K.H.
22yo F
headaches, vomiting
right lateral ventricle
7. R.G.
36 yo M
dizziness
8. N.F.
68 yo M
1.5 yr. left arm weakness
right lateral ventricle cervical cord
subtotal resection XRT: 60 Gy to tumor CCNU 1. XRT (outside hosp.) 2. subtotal resection intraarterial BCNU X4 3. spinal XRT subtotal resection VP shunt XRT: 52.5 Gy to tumor subtotal resection VP shunt chemotx: cytoxan/cisplatin XRT: 54 Gy to tumor, 30 Gy to axis subtotal resection VP shunt chemotx: cytoxan/cisplatin XRT: 54 Gy to tumor, 30 Gy to axis near total resection VP shunt XRT: 54Gy to tumor, 30Gy to axis near total resection biopsy XRT: 43.2 Gy to tumor
A/W 54 mos.
A/W 78 mos. A/W 14 mos.
A/W 11 mos.
A/W 58 mos. A/W 11 m o s .
VP = ventriculoperitoneal; XRT = irradiation therapy; A/W = alive and well.
233
Fig. 1. N e u r o b l a s t o m a : h y p e r c e l l u l a r i n t r a p a r e n c h y m a l t u m o r c o m p o s e d o f s m a l l ceils w i t h h y p e r c h r o m a t i c n u c l e i a n d scant c y t o p l a s m , w i t h s c a t t e r e d p y k n o t i c nuclei. C a s e 2, H a n d E , 425 x .
Fig. 2. N e u r o c y t o m a : m o d e r a t e l y cellular i n t r a v e n t r i c u l a r tum o r c o m p o s e d of cells w i t h u n i f o r m , b l a n d nuclei, p e r i n u c l e a r halos, a n d d e l i c a t e n e u r o f i b r i l l a r y b a c k g r o u n d w i t h a n u c l e a r zones. C a s e 3, H a n d E , 266 x .
were intraparenchymal brain lesions and one was an intramedullary spinal cord lesion; these presented with localizing findings. The pathological data are summarized in Table 2. Cases 1 and 2 were intraparenchymal lesions with necrosis, pyknotic nuclei, and frequent mitotic figures, and were classified as cerebral neuroblastomas (Fig. 1). Cases 5, 6 and 7 were cytolog-
ically bland intraventricular tumors, with prominent clear cell areas and no necrosis or mitotic figures (Fig. 2). Areas of delicate neurofibrillary background with anuclear zones were focally prominent. These correspond to the neurocytomas reported in the literature. Cases 3 and 4 were also classified as intraventricular neurocytomas, but showed additional histologic features such as ne-
Table 2. P a t h o l o g i c a l d a t a Case/Dx
H W rosettes
Ganglion cells
Silver
Mitotic figures
Necrosis
Halos
EM
1. N e u r o b l a s t o m a 2. N e u r o b l a s t o m a
++ rare
-
focal -
++ ++
+ + ++
focal
* NRL
3. N e u r o c y t o m a 4. N e u r o c y t o m a
rare + +
-
* *
-
++ ++
++ focal
NRL NRL
5. N e u r o c y t o m a
++
.
focal
*
6. N e u r o c y t o m a 7. N e u r o c y t o m a
rare ++
-
focal ++
NRL *
.
. * *
. -
-
Immuno
+ + NSE - NF, GFAP + + NSE - NF, GFAP + + NSE - NF, GFAP, Syn, C h r o m
8. N e u r o c y t o m a
rare
rare
*
-
-
++
NRL
H W r o s e t t e s = H o m e r W r i g h t r o s e t t e s ; Silver = B o d i a n silver i m p r e g n a t i o n ; H a l o s = p e r i n u c l e a r h a l o s (clear cells); E M = e l e c t r o n m i c r o s c o p i c d a t a ; I m m u n o = i m m u n o h i s t o c h e m i c a l data;* = d a t a n o t a v a i l a b l e ; ( + + ) = p r e s e n t ; ( - ) = a b s e n t ; N R L = n e u r o n a l f e a t u r e s : cell p r o c e s s e s w i t h m i e r o t u b u l e s a n d d e n s e - c o r e g r a n u l e s ; N S E = n e u r o n - s p e c i f i c e n o l a s e ; N F = n e u r o f i l a m e n t p r o t e i n ; G F A P = glial fibrillary acidic p r o t e i n ; Syn = s y n a p t o p h y s i n ; C h r o m = c h r o m o g r a n i n .
234
Fig. 3. Neurocytoma: Homer Wright rosette areas in an intraventricular tumor. Rare cells in this field show perinuclear clearing (left center). Case 5, H and E, 670 x.
crosis, rare clear cell areas, and/or increased cellularity. Homer Wright rosettes were present in both the neuroblastomas and neurocytomas (Fig. 3). Case 8 histologically resembled a neurocytoma but was located in the spinal cord. Immunohistochemical studies showed all three tumors studied (cases 4, 5 and 7) to be NSE-positive and GFAP-negative. These tests were helpful in ruling out GFAP-positive tumors such as astrocytoma, subependymoma and ependymoma, but were not helpful in the differential diagnosis of oligodendroglioma. The positive NSE results did not aid in the diagnosis because of the lack of specificity of NSE staining. Monoclonal antibodies to synaptophysin and chromogranin failed to stain the one lesion studied. Electron microscopy showed cells with a high nuclear: cytoplasmic ratio, round nuclei with clumped chromatin, and rosette formation with central neurofibrillary cores (Fig. 4a). Cell processes contained microtubules and dense core granules in each case examined (cases 2, 3, 4, 6 and 8) (Fig. 4b). In case 3, synaptic vesicles were noted (Fig. 4c). In cases 3, 6 and 8, the light microscopy had suggested oligodendroglioma, but the electron microscopy findings were diagnostic of neuronal differentiation. No uniform therapeutic protocol was employed. All patients, except case 8, underwent a surgical
resection and radiation therapy. The intraparenchymal lesions (cases 1 and 2) received either BCNU or CCNU. Case 2 originally presented with an intraparenchymal temporal lobe lesion, and returned with systemic metastasis to the T l l vertebral body, which was treated with radiation therapy. Cases 3, 4, and 5 were treated with subtotal resection followed by radiation therapy. Cases 4 and 5 were treated with chemotherapy prior to irradiation. Near total resections were performed on cases 6 and 7, and the spinal cord lesion (case 8) was biopsied and irradiated. Most patients with intraventricular tumors were evaluated with myelography and then treated with craniospinal irradiation. Of the five patients with intraventricular tumors, three have been followed for 14 months or less, but are without clinical deficits at this time; the other two patients, including one tumor with necrosis, show no evidence of progression at 58 months and 78 months. Those patients with intraparenchymal lesions have fared less well: case i died after 1 year of metastatic prostate cancer, and case 2 died of recurrent neuroblastoma 42 months after diagnosis. The patient with the intramedullary cervical cord lesion has done well, with no progression at 54 months.
Discussion
Neuroblastomas are tumors composed of neuronal precursor cells [1-4]. These cells are often poorlydifferentiated and may show only a few neuronal features by electron microscopy [5-7]. Horten and Rubinstein's and Bennett and Rubinstein's seminal studies of cerebral neuroblastomas reported a group of CNS tumors which occurred primarily in children in the first decade of life and which resembled medulloblastoma by light microscopy [8, 9]. The tumors were predominantly intraparenchyreal lesions which followed aggressive courses, although occasional long survivals were noted. Subsequent reports have confirmed these characteristics, and have cited their uncommon occurence in adults [5-7, 10-12]. Reports of a wider spectrum of CNS small-cell
235
Fig. 4: Neurocytoma: 4a. Electron micrograph of Homer Wright rosette showing tumor cells with high nuclear: cytoplasmic ratio, round nuclei with clumped chromatin, and central neurofibrillary core of tumor cell processes. Case 4, 1600 x. 4b. Tumor cell processes containing microtubules and dense core granules. Case 6, 19350 x. 4c. Tumor cell processes with synaptic vesicles and microtubules. Case 3, 15570 ×.
236 neuronal tumors, however, have increased over the past ten years [5-7, 11-26]. From these cases, it is apparent that CNS neuronal tumors may assume a wider variety of forms than previously described, both clinically and pathologically. Hassoun et al. first documented two tumors which were neuroblastic by EM, but which resembled oligodendroglioma rather than medulloblastoma by light microscopy [16]. They termed this tumor 'central neurocytoma,' stressing both the relatively mature appearing neuronal population of the tumor cells and the relatively benign clinical course. Other authors have documented similar cases [7, 18-20, 24-26]. The neurocytomas, unlike most CNS neuroblastomas, occur predominantly in patients in the second and third decades of life and tend to be found in the lateral ventricles. These tumors follow more benign courses that the neuroblastomas, and may in some cases be cured by excision alone. Some papers have stated that the light microscopic picture of the central neurocytoma is nearly identical to that of oligodendroglioma [19, 24]. We would, however, stress the following differences: 1. The nuclei are more varied and euchromatic in the neurocytomas. 2. The fibrillary background is more extensive and more delicate in the neurocytomas, with anuclear zones. 3. The neurocytoma vasculature is delicate and usually inconspicuous, compared with the intricate, prominent branching pattern of the oligodendroglioma. Ultrastructurally, the neurocytoma contains well-differentiated cells [7, 16, 20, 24, 25] which resemble small neurons to the extent of sometimes showing synapse formation [7, 16, 25]. In a cytogenetic scheme, these tumors can be viewed in two ways: 1. The cells of neurocytoma could be neuronal cells intermediate between those immature cells of the neuroblastoma and those mature cells of the gangliocytoma. In this regard, maturing cortical neuroblasts in human fetal brain sometimes show distinct perinuclear halos, while the less mature germinal matrix cells do not. In addition, oligodendroglioma-like areas in medullo-
blastomas have recently been shown to be neuroblastic by immunohistochemical markers [27], and perhaps represent maturation toward a mature cerebellar granular cell. While the perinuclear halos are probably artefactual, they nonetheless may reflect a tendency for more mature neuroblasts to display perinuclear halos in formalin-fixed, paraffin-embedded material. . The cells of the neurocytoma may instead be mature cells which resemble small granular neurons rather than large pyramidal or ganglionic cells. The location of neurocytomas in the area of the fetal germinal matrix suggests that they may arise from residual, committed small neuronal cells remaining along the ventricular surface. In this regard, they are perhaps akin to the subependymal giant cell tumor associated with tuberous sclerosis or even the subependymoma - two other relatively benign ventricular wall tumors that seem to have arisen from the area of the original matrix. The spinal cord tumor appears to be the first neurocytoma to be reported outside of the intracranial ventricular system and could have arisen from cells adjacent to the central canal- an area like the supratentorial germinal matrix, in which neuronal precursor cells were present in fetal life. In summary, there exists a histologically and clinically heterogeneous group of small-celled neuronal CNS tumors. One group has suggested that these tumors might be graded, with grade 4 corresponding to a poorly-differentiated tumor such as a PNET with focal neuronal differentiation, and grade 1 corresponding to the so-called neurocytoma [7]. In such a system, our cases i and 2 would be grade 4, cases 3 and 4 would be intermediate grade primarily because of the necrosis, and cases 5, 6, 7, and perhaps 8 would be grade 1. Cases 3 and 4, however, have done as well clinically as the intraventricular tumors without necrosis. In fact, the location and lack of mitotic activity may be more important than the presence of necrosis or focal hypercellularity in predicting outcome. In addition, the different location and age predilection between neurocytomas and the typical CNS neuroblastoma of childhood suggests that placing such
238 ular neurocytoma: clinicopathological features of six cases. J Neurosurg 68: 665-670, 1988 25. Kubota T, Kawano H, Hayashi M. Cerebral neurocytornalight, electron microscopic and irnrnunohistochemical features (abstract). J Neuropath Exp Neurol 47: 376, 1988 26. Ferreol E, Sawaya R, de Courten-Myers GM. Primary cerebral neuroblastorna (neurocytoma) in adults. J NeuroOnc 7: 121-128, 1989 27. Katsetos CD, Herman MM, Frankfurter A, Gass P, Collins VP, Walker CC, Rosernberg S, Barnard RO, Rubinstein
LJ. Cerebellar desrnoplastic rnedulloblastorna - a further irnrnunohistochernical characterization of the reticulin-free islands. Arch Pathol Lab Med 113: 1019-1029, t989
Address for offprints: D.N. Louis, Dept of Pathology (Neuropathology), Warren 3, Massachusetts General Hospital, Boston, MA 02114, USA
