Journal of Neuro-Oncology 13: 23%246, 1992. © 1992KluwerAcademic Publishers. Printedin the Netherlands. Clinical Study
Intraventricular neurocytoma: four cases report Wen-Ching Tzaan, Yat-Sen Ho 1, Chen-Nen Chang, Tzu-Kang Lin and Cheuk-Wah Wong Division of Neurosurgery, Department of Surgery Department of Pathology 1, Chang Gung Memorial Hospital, Taipei, Taiwan, R. O. C.
Key words: intraventricular neurocytoma, clinicopathological features, immunochemical stain, ultrastructure, oligodendroglioma, neuroblastoma Summary
Intraventricular neurocytoma, a newly identified disease entity with probably not so rare incidence, has several distinctive clinico-pathological characteristics. Four cases are presented. As in the other cases reported in the literature [1-7], the characteristic features are young age, location close to the junction of the septum pellucidum and foramen of Monro, and well-differentiated neuronal origin pathologically.
Introduction
A rather benign tumor of brain, probably misdiagnosed as oligodendroglioma or ependymoma in the past, was brought to attention when the term 'central neurocytoma' was coined by Hassoun et al. [2] in 1982. Four cases are presented. They had rather similar clinical, radiological, and pathological features to those in the literature [1-7]. The distinctive aspects of this tumor and the differential diagnosis with oligodendroglioma, ependymoma and differentiated neuroblastoma will be discussed.
in paraffin. Sections of 6/xm in thickness were cut and stained with hematoxylin and eosion (H&E). For immunochemistry, paraffin sections were stained with primary antiserum directed against glial fibrillary acidic protein (GFAP), Leu-7, S-100 protein, neuron-specific enolase (NSE), neurofilament (NF) and synaptophysin according to the avidin-biotin-peroxidase method. Samples for electron microscopy (EM) were fixed in 2% glutaraldehyde and embedded in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate.
Results Materials and methods
Four patients with intraventricular tumors, were admitted to Chang Gung Memorial Hospital between 1989 and 1990. They received clinical assessment, radiological studies with computed tomographic (CT) scan and cerebral digital subtraction angiography (DSA), and surgery. The latest postoperative follow-up was done in April 1991. The pathological specimen obtained at surgery was fixed in 10% buffered formalin and embedded
The clinical features of the four cases are summarized in Table 1. All of them were young adults aged between 23 and 35 years. Equal sex distribution was noted. All the patients presented with headache. Two of them also complained of blurring of vision with insidious onset. The duration of symptoms ranged from 10 days to 4 years. No focal neurological deficit but papilledema was noted in all these patients. Radiologically, CT scan revealed hydrocephalus
240
Fig. 1. Pre-enhancement (Case 1) axial CT scan demonstrating ventricular dilatation and a tumor with heterogenous density and heavy calcification located at body of both lateral ventricle and around the foramen of Monro.
and a heterogenous mass occupying the anterior and/or midportion of the lateral ventricles with obstruction of foramen of Monro (Fig. 1). In two of the cases, the tumor extended into third ventricle (Case 2 and 3). Moderate to heavy degrees of calcified density were noted in all cases. Enhancement by contrast medium in the isodense portion of the tumor was the rule (Fig. 2). The CT scan characteristics are summarized in Table 2. Cerebral DSA revealed rather strong tumor stain fed by anterior
and posterior choroidal arteries (Fig. 3). No magnetic resonance images (MRI) were performed in these cases. A fronto-parietal craniotomy with transcallosal approach for tumor excision was done in these patients. Intraoperatively, the tumor appeared grayish and richly vascularized. It was removable by suction but bled rather easily. Small cysts within the tumor were noted in one case (Case 1). One patient (Case 2) received total excision and the
Table 1. The clinical features of the four cases. Case
Age (Yrs)
Sex
Symptom
Sign
Duration
Operation
R/T
Complication
Follow-up (months)
Condition
1
32
M
H+ V
P
4 yrs
S
+
hydro.
24
2 3
23 35
F F
H+ E H+ V
P P
1 mon 1 mon
T S
+
18
4
33
M
H
P
10 days
S
+
EDH brain swelling/ expired hydro.
well, except poor vision good
6
good
M: Male, F: Female, P: Papilledema, E: Emesis, H: Headache, V: Blurring of vision, T: Total excision, S: Subtotal excision, R/T: Post-operative radiotherapy, Hydro.: Hydrocephalus, EDH: Epidural hematoma.
241
Fig. 2. P o s t - e n h a n c e m e n t C T scan showing (Case 1) significant e n h a n c e m e n t of the isodense portion of the t u m o r after intravenous injection of contrast material.
other three underwent subtotal excision of tumor. One patient (Case 3) expired a few days after operation, death was attributed to brain swelling. The other three patients had postoperative complications as listed in Table 1. The complications were corrected satisfactorily. Radiotherapy was performed in these three cases. During the follow-up period of 6 to 24 months, all three were neurologically stable and lived a good life. No recurrence of tumor were noted in their follow-up CT scans.
Pathological and ultrastructural findings Grossly, the tumors were mainly grayish and friable and in some areas were firm and white in color. Under light microscopy, they appeared to have rather monomorphous cell populations (Fig. 4). Cell contours were round and their margins were well defined. Centrally located nuclei were regularly round with fine heterochromatin. Perinuclear halos were characteristic. The cells were clustered by fine connective tissue trabeculum and capillaries. Mitosis was infrequent. Calcification was usually noted. Immunohistochemical stain revealed a
Table 2. T h e characteristics of C T scan picture of the four cases. Case
Location
Hydrocephalus
Calcification
Enhancement
1
2 3 4
B
+
+
+
L + 3rd L + 3rd L
+ + +
+ + +
+ + +
B: Bilateral lateral ventricle, L: Left lateral ventricle. 3rd: Third ventricle.
242
Fig. 4. Light microscopic picture of the tumor (Case 1) demonstrating monomorphous tumor cells embedded in fine fibrillary stroma. The characteristic perinuelear halo and calcification were noted (C:calcification) (H&E origin x 100).
Table 3. Electron microscopic examination (EM) confirmed that the tumor ceils were of neuronalorigin (Fig. 5). Their cytoplasm contained numerous membrane-bound neurosecretory granules, and interdigitating cytoplasmic processes contained microtubules clear vesicles, and dense-core granules. Abortive synapses between cell junction were distinctive. Table 4 lists the EM characteristics of the four patients.
Fig. 3. DSA (Case 1) showing significant tumor staining at the late arterial and capillary phase.
neuronal-origin character, that was strongly positive with NSE and NF staining, weakly positive with S-100 and Leu-7. GFAP staining was only reactive to some astrocytes within the tumor. Synaptophysin was positive in the pericytoplasmic membrane of soma and processes of tumor cells in these four cases. The results of immunohistochemical stain of the four patients are summarized in
Discussion
In 1982, Hassoun et al. first presented two cases and coined the term 'central neurocytoma' [2]. In 1985, Wilson et al. presented one similar case but it had no synapses under EM and was diagnosed as differentiated neuroblastoma [8]. In 1986, Townsend et
Table 3. The results of immunohistochemical stain of the four cases. Case No.
GFAP
Leu-7
NF
l
-
+*
+
2 3 4
-
+* +* +*
+ + +
+ : Positive, +* :Weakly positive, - : Negative, GFAP: Glial fibrillary acidic protein, NSE: Neuron-specific enolase, NF: Neurofilament.
Vimentin
Synaptophysin
S-100
NSE
+ + + +
+* +* +* +*
+ + + +
243 al. presented two cases and thought defined syn-
apses was one of the dividing points between the neurocytoma and the differentiated neuroblastoma [5]. In 1988, Nishio et al. presented six cases which were revised from the previous diagnosis of oligodendroglioma [3]. All six cases showed negative reaction to neurofilament and NSE and no well-formed synapses were identified under EM. However, they had prolonged survival, including one patient who are well for nearly 19 years. They proposed that there might be a certain range of differentiation in this tumor. To avoid nosological confusion, therefore, they preferred the term 'intraventricular neurocytoma'. In 1990, Patil et al. presented two cases and described the MRI picture [4]. The same year, Barbosa et al. presented three cases [1]. Two of them were also revised from a previous diagnosis of oligodendroglioma. They added synaptophysin in the immunohistochemical stain examination. Two cases were positive with synaptophysin. Our four cases and the 34 cases reported in the reviewed literature [1-7], a total of 38 cases, presented mainly with the symptoms of intracranial hypertension, ie. headache, vomiting and blurring of vision. Just like other intraventricular tumors, focal neurological deficits were only noted in a few of the cases of intraventricular neurocytoma. Neurocytoma is similar to oligodendroglioma and ependymoma under light microscope (H&E), especially the former. They are usually hard to distinguish by this means only. Some of the cases of neurocytoma reported in the literature, as described above, were revised from the previous diagnosis of oligodendroglioma [1, 3]. On the basis of the 38 cases, the distinctive features of neurocyto-
Fig. 5. E M picture of the t u m o r (Case 3) showing tumor cells, their abortive synapse and cytoplasmic processes containing clear vesicles (long arrows), dense-core granules (short arrows) and microtubules (arrowheads) N:nucleus. ( x 16000).
ma and its comparison with oligodendroglioma are presented. 1. Age: Almost all the cases of neurocytoma were young adults ranging in age from 15 to 53 years. Among them, 29 cases (about 76%) were between 21 to 39 years, the mean age was 28.6 years. No sex predilection was noted. Most oligodendrogliomas occur in adults in their third, fourth or fifth decades. In most series, the mean age is between 38 and 45 years [9]. There is a slight predominance of males in most series. Neurocytomas seem to occur in a slightly younger and narrower age range than oligodendroglioma. 2. Radiological findings: In neurocytomas, the CT scan showed a heterogenous and irregularly shaped mass located in the lateral ventricle. The
Table 4. The E M characteristics of the four cases. Case No.
Microtubules
Densecore granules
Clear vesicles
Abortive synapses structures
l 2 3 4
+ + + +
+ + + +
+ + + +
+ + + _
+ : Found, - : Not found.
244 foramen of Monro was usually obstructed with accompanying hydrocephalus. Calcification within the tumor was common and varied in intensity. The degree of enhancement of the tumors was slight to moderate. The tumors might involve the third ventricle through the foramen of Monro. All neurocytomas were specifically located at the anteromedial portion of the body of the lateral ventricle. They always had contact with the junction of septum pellucidum and foramen of Monro. A close attachment or an indistinct tissue plane between the neurocytomas and the posterior part of septum pellucidum were the common intraoperative findings. They were identified as arising from this particular site in the cases of Nashio, et al. [3], Patil et al. [4] and Barbosa, et al. [1]. The original hypothesis of Hassoun et al. [2], that the nuclei of the septum pellucidum could be a possible source of the tumor, gained further support from these subsequent case reports. This central origin may be explained by the sequence of neuronal development. Kinney et al. have identified the sequence of myelination in the brain [10]. The myelination progresses from the central sulcus outward toward the poles. It may explain the tendency of central location of neurocytoma. Neurocytomas usually presented a tumor stain on cerebral angiography and were fed by anterior and/ or posterior choroidal arteries. Patil etal. described the isodensity of the tumor with cerebral cortex on both T1 and T2 weighted and proton density images [4]. In addition, serpiginous signal voids and characteristically large draining veins were mentioned. Oligodendrogliomas occur anywhere that oligodendrocytes are found, and more than 80% are localized in the white matter of a cerebral hemisphere [11]. The frontal lobe is the most common location; only 3% developed in the lateral ventricle. Case reports of the primary intraventricular oligodendroglioma have been presented in the past, but they did not have an EM diagnosis [1216]. Some of the cases were young adults, and the tumors were located at the medial portion of the
lateral ventricle and had benign behavior. There might be misdiagnosis among them, as in those revised cases mentioned previously. The CT scan presentation of the intraventricular oligodendroglioma as described in the literature [12-16] is similar to neurocytoma. On MRI, however, oligodendroglioma is hypointense on T1weighted images and hyperintense on T2-weighted images except for regions of signal void that correspond to calcium fragments [11]. Angiography shows an avascular mass with intraventricular oligodendroglioma. 3. Pathology: Grossly, neurocytomas were grayish and vascularized in noncalcified area. They were easy to aspirate. Under light microscope, they appeared as mono-morphous small cells with central round nuclei and fine chromatin. Perinuclear halos were characteristic. Capillary networks formed incomplete septa. Mitoses were absent or infrequent. Pseudorosettes were described in some cases [1, 5, 6]. Focal necrosis was only noted in few cases [4, 6, 7]. The pathological picture of oligodendrogliomas are also characterized by small cells with perinuclear halos. They are similar to neurocytomas, so it is usually hard to distinguish between them. An immunohistochemical stain will help. Neurocytoma may or may not be reactive to neurofilament protein and NSE. GFAP is only positive in some scattered reactive astrocytes within and at the periphery of this tumor. Synaptophysin, the glycoprotein component of the membrane of presynaptic vesicles, has been used as a marker of neuroendocrine cells and their neoplasms [17-19]. Our four and two of Barbosa's cases were positive with synaptophysin. It may be another promising marker. About half of the oligodendrogliomas are positive with GFAP. Some of the oligodendrogliomas are also reactive to NSE. As for Leu-7 and S-100, both neuronal and glial tumors show more variable reactivity. Under EM, the most constant finding of neurocytomas were synapses and abundant cell processes containing microtubules, dense-core granules and clear vesicles. Except for microtubules, oligodendrogliomas also have laminated myelin structure, although it is not specific. But
245 they don't have synapses and neurosecretory granules. The different ultrastructural presentation of these two tumors is distinct. For differentiation with ependymoma, the perivascular acellular eosinophilic fibrillary zone of the neurocytoma may also mimic the nuclear free perivascular zone of the former. But it is a fine mesh network in neurocytoma and is not like the radially oriented processes in ependymoma. Using immunohistochemical stains, ependymoma is positive with GFAP and its pseudorosettes are intensely positive with S-100. Under EM, cilia and microvilli fill the lumen of ependymal rosettes. Intercellular junctions are prominent near the luminal surface of the tumor cells. The basal body of the cilium is also noted in ependymoma [20]. According to the report of Bennett et al., 80% of the primary cerebral neuroblastomas occur in the first decade of life, and most often before the age of 2 years [21]. The frontal or parietal parenchyma are the most common location. The intraventricular location of neuroblastoma had been reported in the literature [8, 21-23]. There were 11 cases, all of whom were young adults, except one infant [21]. The age range was from 1 1/2 to 52 years. Among them, eight patients (about 73%) were between 16 and 29-years-old. This age distribution is quite different from that of neuroblastomas in other intracranial locations, but similar to that of intraventricular neurocytoma. These central neuroblastomas were located at various parts of the lateral or third ventricle. Their location is much more variable than that of neurocytoma. Under light microscope, small hyperchromatic cells embedded within a meshwork of fine cellular processes, and Homer Wright rosettes in some cases, were identified. NSE reactivity varied. Ultrastructurally, they either had or did not have cell processes containing microtubules, dense-core granules and clear vesicles. Some cases did have abortive or even typical synapses while others had no synapses [22, 23]. They presented with various degrees of differentiation. Synapses, cell processes, microtubules and membrane-bound neurosecretory granules are the features which can be used to determine the degree
of differentiation. Among them, synapses are the indicator of a greater degree of differentiation [22]. Neurocytomas are the most differentiated form. They have typical synapses and interdigitating cell processes containing parallel microtubules and dense-core granules. These tumors were seen in those cases reported by Hassoun et al. [2], Townsend et al. [5], Kubota et al. [6] and Von Deimling et al. [7]. Our four cases and the other neurocytomas reviewed had no synapses or only had abortive synapses. They were similar clinico-pathologically to the cases of differentiated neuroblastoma reported by Jerdan et al. [24] and Wilson et al. [8]. Nishio et al. thought that to avoid nosological confusion, the term 'neurocytoma' was preferred for these not so well differentiated tumors [3]. On this basis, certain cases of intraventricular neuroblastoma that had better differentiated structures should be revised to neurocytoma. These cases were seen in the report of Pooh et al. [23] and Pearl et al. [22]. It should be emphasized that not all intraventricular neuroblastomas have such differentiation. Therefore, it is not a synonym for intraventricular neurocytoma.
Conclusion
Neurocytoma is a slow growing tumor and has a good prognosis after surgical excision. The immunohistochemical stain is an adjunctive diagnostic tool. The final diagnosis depends on the ultrastructural picture under EM. Theoretically, it can occur in locations other than the ventricle. Some of the oligodendrogliomas and ependymomas diagnosed previously without EM examination might actually be neurocytomas. Therefore, routine EM examination in the cases presenting the histological picture of these tumors may give the answer, especially when immunohistochemical stains give equivocal results. The true incidence and prognosis depends on more cases being collected and a prolonged period of follow-up.
246 References 1. Barbosa MD, Balsitis M, Jaspan T, Lowe J: Intraventricular neurocytoma: a clinical and pathological study of three cases and review of the literature. Neurosurgery 26: 10451054, 1990 2. Hassoun J, Gambarelli D, Grisoli F, Pellet W, Salamon G, Pellissier JF, Toga M: Central neurocytoma. Acta Neuropathol (Berl) 56: 151-156, 1982 3. Nishio S, Tasbima T, Takeshita I, Fukui M: Intraventricular neurocytoma: clinico-pathological features of six cases. J Neurosurg 68: 665-670, 1988 4. Patil AA, McComb RD, Gelber B, McConnell J, Sasse S: Intraventricular neurocytoma: a report of two cases. Neurosurgery 26: 140-144, 1990 5. Townsend J J, Seaman JP: Central neurocytoma. Acta Neuropathol (Berl) 71: 167-170, 1986 6. Kubota T, Hayashi M, Kawano H, Kabuto M, Sato K, Ishise J, Kawamoto K, et al. : Central neurocytoma: immunohistochemical and ultrastructural study. Acta Neuropathol 81: 418-427, 1991 7. Von Deimling A, Janzer R, Kleihues P, Wiestler OD: Patterns of differentiation in central neurocytoma. Acta Neuropathol 79: 473-479, 1990 8. Wilson A J, Leafier DH, Kohout ND: Differentiated cerebral neuroblastoma: a tumor in need of discovery. Human Pathology 16: 647-649, 1985 9. Mansuy L, Thierry A, Tommasi M: Oligodendroglioma. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology. Tumors of the Brain and Skul, Vol 18 Part lI, North-Holland Publishing Co., Amsterdam, 1975, pp 81103 10. Kinney HC, Brody BA, Kloman AS, Gilles FH: Sequence of central nervous system myelination in human infancy. J Neuropathol Exp Neurol 47: 217-234, 1988 1l. Harsh IV GR, Wilson CB: Neuroepithelial tumors of the adult brain. In: Youmans JR (eds) Neurological Surgery. Vol. 5: 3rd ed. Saunders, Philadelphia, 1990, pp 3105-3107 12. Dolinskas CA, Simeone FA: CT Characteristics of intraventricular oligodendrogliomas. AJNR 8: 1077-1082, 1987
13. Hasuo K, Fukui M, Tamura S, Yasumori K, Uchino A, Nahagohi H, Qgawa H, Nagasaha S, Masuda K: Oligodendrogliomas of the lateral ventricle: computed tomography and angiography. J Comput Tomo 11: 376-382, 1987 14. Kikuchi K, Kowada M, Mineura K, Uemura K: Primary oligodendroglioma of the lateral ventricle with computed tomographic and positron emission tomographic evaluation. Surg Neurol 23: 483-488, 1985 15. Markwalder TM, Huber P, Markwalder RV, Seiler RW: Primary intraventricular oligodendrogliomas. Surg Neurol 11: 25-28, 1979 16. Maiuri F, Giamundo A, Prisco BD: Primary intraventricular oligodendroglioma. Surg Neurol 18: 364-366, 1982 17. Gould VE, Lee 1, Wiedenmann B, Moll R, Chejfee G, Franke WW: Synaptophysin: a novel marker for neurons, certain neuroendocrine cells, and their neoplasms. Human Pathology 17: 979-983, 1986 18. Gould VE: Synaptophysin: a new and promising pan-neuroendocrine marker. Arch Pathol Lab Med 111: 791-794, 1987 19. Miettinen M: Synaptophysin and neurofilament proteins as markers for neuroendocrine tumors. Arch Pathol Lab Med 111: 813-818, 1987 20. Tabuchi K, Nishimoto A: Ependymoma. In: Tabuchi K, Nishimoto A (eds) Atlas of Brain Tumors. Springer-Verlag, Berlin, 1988, pp 41-48. 21. Bennett JP, Rubinstein LT: The biological behavior of primary cerebral neuroblastoma: a reappraisal of the clinical course in a series of 70 cases. Ann Neurol 16: 21-27, 1984 22. Pearl GS, Takei Y, Bakay RAE, Davis P: Intraventricular primary cerebral neuroblastoma in adults: report of three cases. Neurosurg 16: 847-849, 1985 23. Poon TP, Mangiardi JR, Matoso I, Weitzner l: Third ventricular primary cerebral neuroblastoma. Surg Neurol 30: 237-241, 1988 24. Jerdan MS, White CL IfI, Solomon D, etal. : Differentiated cerebral neuroblastoma in adults. (abstract). J Neuropathol Exp Neurol 42: 305, 1983 Address for offprints: Wen-Ching Tzaan, M.D., Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, 199 Tun Hwa North Road, Taipei, Taiwan, R.O.C. 10591
Intraventricular neurocytoma: four cases report Wen-Ching Tzaan, Yat-Sen Ho 1, Chen-Nen Chang, Tzu-Kang Lin and Cheuk-Wah Wong Division of Neurosurgery, Department of Surgery Department of Pathology 1, Chang Gung Memorial Hospital, Taipei, Taiwan, R. O. C.
Key words: intraventricular neurocytoma, clinicopathological features, immunochemical stain, ultrastructure, oligodendroglioma, neuroblastoma Summary
Intraventricular neurocytoma, a newly identified disease entity with probably not so rare incidence, has several distinctive clinico-pathological characteristics. Four cases are presented. As in the other cases reported in the literature [1-7], the characteristic features are young age, location close to the junction of the septum pellucidum and foramen of Monro, and well-differentiated neuronal origin pathologically.
Introduction
A rather benign tumor of brain, probably misdiagnosed as oligodendroglioma or ependymoma in the past, was brought to attention when the term 'central neurocytoma' was coined by Hassoun et al. [2] in 1982. Four cases are presented. They had rather similar clinical, radiological, and pathological features to those in the literature [1-7]. The distinctive aspects of this tumor and the differential diagnosis with oligodendroglioma, ependymoma and differentiated neuroblastoma will be discussed.
in paraffin. Sections of 6/xm in thickness were cut and stained with hematoxylin and eosion (H&E). For immunochemistry, paraffin sections were stained with primary antiserum directed against glial fibrillary acidic protein (GFAP), Leu-7, S-100 protein, neuron-specific enolase (NSE), neurofilament (NF) and synaptophysin according to the avidin-biotin-peroxidase method. Samples for electron microscopy (EM) were fixed in 2% glutaraldehyde and embedded in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate.
Results Materials and methods
Four patients with intraventricular tumors, were admitted to Chang Gung Memorial Hospital between 1989 and 1990. They received clinical assessment, radiological studies with computed tomographic (CT) scan and cerebral digital subtraction angiography (DSA), and surgery. The latest postoperative follow-up was done in April 1991. The pathological specimen obtained at surgery was fixed in 10% buffered formalin and embedded
The clinical features of the four cases are summarized in Table 1. All of them were young adults aged between 23 and 35 years. Equal sex distribution was noted. All the patients presented with headache. Two of them also complained of blurring of vision with insidious onset. The duration of symptoms ranged from 10 days to 4 years. No focal neurological deficit but papilledema was noted in all these patients. Radiologically, CT scan revealed hydrocephalus
240
Fig. 1. Pre-enhancement (Case 1) axial CT scan demonstrating ventricular dilatation and a tumor with heterogenous density and heavy calcification located at body of both lateral ventricle and around the foramen of Monro.
and a heterogenous mass occupying the anterior and/or midportion of the lateral ventricles with obstruction of foramen of Monro (Fig. 1). In two of the cases, the tumor extended into third ventricle (Case 2 and 3). Moderate to heavy degrees of calcified density were noted in all cases. Enhancement by contrast medium in the isodense portion of the tumor was the rule (Fig. 2). The CT scan characteristics are summarized in Table 2. Cerebral DSA revealed rather strong tumor stain fed by anterior
and posterior choroidal arteries (Fig. 3). No magnetic resonance images (MRI) were performed in these cases. A fronto-parietal craniotomy with transcallosal approach for tumor excision was done in these patients. Intraoperatively, the tumor appeared grayish and richly vascularized. It was removable by suction but bled rather easily. Small cysts within the tumor were noted in one case (Case 1). One patient (Case 2) received total excision and the
Table 1. The clinical features of the four cases. Case
Age (Yrs)
Sex
Symptom
Sign
Duration
Operation
R/T
Complication
Follow-up (months)
Condition
1
32
M
H+ V
P
4 yrs
S
+
hydro.
24
2 3
23 35
F F
H+ E H+ V
P P
1 mon 1 mon
T S
+
18
4
33
M
H
P
10 days
S
+
EDH brain swelling/ expired hydro.
well, except poor vision good
6
good
M: Male, F: Female, P: Papilledema, E: Emesis, H: Headache, V: Blurring of vision, T: Total excision, S: Subtotal excision, R/T: Post-operative radiotherapy, Hydro.: Hydrocephalus, EDH: Epidural hematoma.
241
Fig. 2. P o s t - e n h a n c e m e n t C T scan showing (Case 1) significant e n h a n c e m e n t of the isodense portion of the t u m o r after intravenous injection of contrast material.
other three underwent subtotal excision of tumor. One patient (Case 3) expired a few days after operation, death was attributed to brain swelling. The other three patients had postoperative complications as listed in Table 1. The complications were corrected satisfactorily. Radiotherapy was performed in these three cases. During the follow-up period of 6 to 24 months, all three were neurologically stable and lived a good life. No recurrence of tumor were noted in their follow-up CT scans.
Pathological and ultrastructural findings Grossly, the tumors were mainly grayish and friable and in some areas were firm and white in color. Under light microscopy, they appeared to have rather monomorphous cell populations (Fig. 4). Cell contours were round and their margins were well defined. Centrally located nuclei were regularly round with fine heterochromatin. Perinuclear halos were characteristic. The cells were clustered by fine connective tissue trabeculum and capillaries. Mitosis was infrequent. Calcification was usually noted. Immunohistochemical stain revealed a
Table 2. T h e characteristics of C T scan picture of the four cases. Case
Location
Hydrocephalus
Calcification
Enhancement
1
2 3 4
B
+
+
+
L + 3rd L + 3rd L
+ + +
+ + +
+ + +
B: Bilateral lateral ventricle, L: Left lateral ventricle. 3rd: Third ventricle.
242
Fig. 4. Light microscopic picture of the tumor (Case 1) demonstrating monomorphous tumor cells embedded in fine fibrillary stroma. The characteristic perinuelear halo and calcification were noted (C:calcification) (H&E origin x 100).
Table 3. Electron microscopic examination (EM) confirmed that the tumor ceils were of neuronalorigin (Fig. 5). Their cytoplasm contained numerous membrane-bound neurosecretory granules, and interdigitating cytoplasmic processes contained microtubules clear vesicles, and dense-core granules. Abortive synapses between cell junction were distinctive. Table 4 lists the EM characteristics of the four patients.
Fig. 3. DSA (Case 1) showing significant tumor staining at the late arterial and capillary phase.
neuronal-origin character, that was strongly positive with NSE and NF staining, weakly positive with S-100 and Leu-7. GFAP staining was only reactive to some astrocytes within the tumor. Synaptophysin was positive in the pericytoplasmic membrane of soma and processes of tumor cells in these four cases. The results of immunohistochemical stain of the four patients are summarized in
Discussion
In 1982, Hassoun et al. first presented two cases and coined the term 'central neurocytoma' [2]. In 1985, Wilson et al. presented one similar case but it had no synapses under EM and was diagnosed as differentiated neuroblastoma [8]. In 1986, Townsend et
Table 3. The results of immunohistochemical stain of the four cases. Case No.
GFAP
Leu-7
NF
l
-
+*
+
2 3 4
-
+* +* +*
+ + +
+ : Positive, +* :Weakly positive, - : Negative, GFAP: Glial fibrillary acidic protein, NSE: Neuron-specific enolase, NF: Neurofilament.
Vimentin
Synaptophysin
S-100
NSE
+ + + +
+* +* +* +*
+ + + +
243 al. presented two cases and thought defined syn-
apses was one of the dividing points between the neurocytoma and the differentiated neuroblastoma [5]. In 1988, Nishio et al. presented six cases which were revised from the previous diagnosis of oligodendroglioma [3]. All six cases showed negative reaction to neurofilament and NSE and no well-formed synapses were identified under EM. However, they had prolonged survival, including one patient who are well for nearly 19 years. They proposed that there might be a certain range of differentiation in this tumor. To avoid nosological confusion, therefore, they preferred the term 'intraventricular neurocytoma'. In 1990, Patil et al. presented two cases and described the MRI picture [4]. The same year, Barbosa et al. presented three cases [1]. Two of them were also revised from a previous diagnosis of oligodendroglioma. They added synaptophysin in the immunohistochemical stain examination. Two cases were positive with synaptophysin. Our four cases and the 34 cases reported in the reviewed literature [1-7], a total of 38 cases, presented mainly with the symptoms of intracranial hypertension, ie. headache, vomiting and blurring of vision. Just like other intraventricular tumors, focal neurological deficits were only noted in a few of the cases of intraventricular neurocytoma. Neurocytoma is similar to oligodendroglioma and ependymoma under light microscope (H&E), especially the former. They are usually hard to distinguish by this means only. Some of the cases of neurocytoma reported in the literature, as described above, were revised from the previous diagnosis of oligodendroglioma [1, 3]. On the basis of the 38 cases, the distinctive features of neurocyto-
Fig. 5. E M picture of the t u m o r (Case 3) showing tumor cells, their abortive synapse and cytoplasmic processes containing clear vesicles (long arrows), dense-core granules (short arrows) and microtubules (arrowheads) N:nucleus. ( x 16000).
ma and its comparison with oligodendroglioma are presented. 1. Age: Almost all the cases of neurocytoma were young adults ranging in age from 15 to 53 years. Among them, 29 cases (about 76%) were between 21 to 39 years, the mean age was 28.6 years. No sex predilection was noted. Most oligodendrogliomas occur in adults in their third, fourth or fifth decades. In most series, the mean age is between 38 and 45 years [9]. There is a slight predominance of males in most series. Neurocytomas seem to occur in a slightly younger and narrower age range than oligodendroglioma. 2. Radiological findings: In neurocytomas, the CT scan showed a heterogenous and irregularly shaped mass located in the lateral ventricle. The
Table 4. The E M characteristics of the four cases. Case No.
Microtubules
Densecore granules
Clear vesicles
Abortive synapses structures
l 2 3 4
+ + + +
+ + + +
+ + + +
+ + + _
+ : Found, - : Not found.
244 foramen of Monro was usually obstructed with accompanying hydrocephalus. Calcification within the tumor was common and varied in intensity. The degree of enhancement of the tumors was slight to moderate. The tumors might involve the third ventricle through the foramen of Monro. All neurocytomas were specifically located at the anteromedial portion of the body of the lateral ventricle. They always had contact with the junction of septum pellucidum and foramen of Monro. A close attachment or an indistinct tissue plane between the neurocytomas and the posterior part of septum pellucidum were the common intraoperative findings. They were identified as arising from this particular site in the cases of Nashio, et al. [3], Patil et al. [4] and Barbosa, et al. [1]. The original hypothesis of Hassoun et al. [2], that the nuclei of the septum pellucidum could be a possible source of the tumor, gained further support from these subsequent case reports. This central origin may be explained by the sequence of neuronal development. Kinney et al. have identified the sequence of myelination in the brain [10]. The myelination progresses from the central sulcus outward toward the poles. It may explain the tendency of central location of neurocytoma. Neurocytomas usually presented a tumor stain on cerebral angiography and were fed by anterior and/ or posterior choroidal arteries. Patil etal. described the isodensity of the tumor with cerebral cortex on both T1 and T2 weighted and proton density images [4]. In addition, serpiginous signal voids and characteristically large draining veins were mentioned. Oligodendrogliomas occur anywhere that oligodendrocytes are found, and more than 80% are localized in the white matter of a cerebral hemisphere [11]. The frontal lobe is the most common location; only 3% developed in the lateral ventricle. Case reports of the primary intraventricular oligodendroglioma have been presented in the past, but they did not have an EM diagnosis [1216]. Some of the cases were young adults, and the tumors were located at the medial portion of the
lateral ventricle and had benign behavior. There might be misdiagnosis among them, as in those revised cases mentioned previously. The CT scan presentation of the intraventricular oligodendroglioma as described in the literature [12-16] is similar to neurocytoma. On MRI, however, oligodendroglioma is hypointense on T1weighted images and hyperintense on T2-weighted images except for regions of signal void that correspond to calcium fragments [11]. Angiography shows an avascular mass with intraventricular oligodendroglioma. 3. Pathology: Grossly, neurocytomas were grayish and vascularized in noncalcified area. They were easy to aspirate. Under light microscope, they appeared as mono-morphous small cells with central round nuclei and fine chromatin. Perinuclear halos were characteristic. Capillary networks formed incomplete septa. Mitoses were absent or infrequent. Pseudorosettes were described in some cases [1, 5, 6]. Focal necrosis was only noted in few cases [4, 6, 7]. The pathological picture of oligodendrogliomas are also characterized by small cells with perinuclear halos. They are similar to neurocytomas, so it is usually hard to distinguish between them. An immunohistochemical stain will help. Neurocytoma may or may not be reactive to neurofilament protein and NSE. GFAP is only positive in some scattered reactive astrocytes within and at the periphery of this tumor. Synaptophysin, the glycoprotein component of the membrane of presynaptic vesicles, has been used as a marker of neuroendocrine cells and their neoplasms [17-19]. Our four and two of Barbosa's cases were positive with synaptophysin. It may be another promising marker. About half of the oligodendrogliomas are positive with GFAP. Some of the oligodendrogliomas are also reactive to NSE. As for Leu-7 and S-100, both neuronal and glial tumors show more variable reactivity. Under EM, the most constant finding of neurocytomas were synapses and abundant cell processes containing microtubules, dense-core granules and clear vesicles. Except for microtubules, oligodendrogliomas also have laminated myelin structure, although it is not specific. But
245 they don't have synapses and neurosecretory granules. The different ultrastructural presentation of these two tumors is distinct. For differentiation with ependymoma, the perivascular acellular eosinophilic fibrillary zone of the neurocytoma may also mimic the nuclear free perivascular zone of the former. But it is a fine mesh network in neurocytoma and is not like the radially oriented processes in ependymoma. Using immunohistochemical stains, ependymoma is positive with GFAP and its pseudorosettes are intensely positive with S-100. Under EM, cilia and microvilli fill the lumen of ependymal rosettes. Intercellular junctions are prominent near the luminal surface of the tumor cells. The basal body of the cilium is also noted in ependymoma [20]. According to the report of Bennett et al., 80% of the primary cerebral neuroblastomas occur in the first decade of life, and most often before the age of 2 years [21]. The frontal or parietal parenchyma are the most common location. The intraventricular location of neuroblastoma had been reported in the literature [8, 21-23]. There were 11 cases, all of whom were young adults, except one infant [21]. The age range was from 1 1/2 to 52 years. Among them, eight patients (about 73%) were between 16 and 29-years-old. This age distribution is quite different from that of neuroblastomas in other intracranial locations, but similar to that of intraventricular neurocytoma. These central neuroblastomas were located at various parts of the lateral or third ventricle. Their location is much more variable than that of neurocytoma. Under light microscope, small hyperchromatic cells embedded within a meshwork of fine cellular processes, and Homer Wright rosettes in some cases, were identified. NSE reactivity varied. Ultrastructurally, they either had or did not have cell processes containing microtubules, dense-core granules and clear vesicles. Some cases did have abortive or even typical synapses while others had no synapses [22, 23]. They presented with various degrees of differentiation. Synapses, cell processes, microtubules and membrane-bound neurosecretory granules are the features which can be used to determine the degree
of differentiation. Among them, synapses are the indicator of a greater degree of differentiation [22]. Neurocytomas are the most differentiated form. They have typical synapses and interdigitating cell processes containing parallel microtubules and dense-core granules. These tumors were seen in those cases reported by Hassoun et al. [2], Townsend et al. [5], Kubota et al. [6] and Von Deimling et al. [7]. Our four cases and the other neurocytomas reviewed had no synapses or only had abortive synapses. They were similar clinico-pathologically to the cases of differentiated neuroblastoma reported by Jerdan et al. [24] and Wilson et al. [8]. Nishio et al. thought that to avoid nosological confusion, the term 'neurocytoma' was preferred for these not so well differentiated tumors [3]. On this basis, certain cases of intraventricular neuroblastoma that had better differentiated structures should be revised to neurocytoma. These cases were seen in the report of Pooh et al. [23] and Pearl et al. [22]. It should be emphasized that not all intraventricular neuroblastomas have such differentiation. Therefore, it is not a synonym for intraventricular neurocytoma.
Conclusion
Neurocytoma is a slow growing tumor and has a good prognosis after surgical excision. The immunohistochemical stain is an adjunctive diagnostic tool. The final diagnosis depends on the ultrastructural picture under EM. Theoretically, it can occur in locations other than the ventricle. Some of the oligodendrogliomas and ependymomas diagnosed previously without EM examination might actually be neurocytomas. Therefore, routine EM examination in the cases presenting the histological picture of these tumors may give the answer, especially when immunohistochemical stains give equivocal results. The true incidence and prognosis depends on more cases being collected and a prolonged period of follow-up.
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