Histol Histopathol (2001) 16: 61 3-622 001 : 10.14670/HH-16.613 Histology and http://www.ehu.es/histol-histopathol Histopathology Cellular and Molecular Biology

Review

Neuronal and mixed neuronal glial tumors associated to epilepsy. A heterogeneous and related group of tumours

A. Morenol, J. de Felipe2, R. Garcia Sola3, A. Navarrol and S. Ramon y Cajal1 1 Department of Pathology, Cllnica Puerta de Hierro, 21nstituto Cajal and 3Hospital de la Princesa, Madrid, Spain

Summary. The group of brain tumors with mature Introduction components encompasses several pathological entities including: the ganglioneuroma; the gangliocytoma; the Brain tumors comprised of mature or immature ganglioglioma; the desmoplastic ganglioglioma; the neuronal cells and associated with a mixed neural and neurocitoma and a group of glioneuronal hamartomatous glia l component are very rare, constituting roughly 1% tumorous lesions, such as meningoangiomatosis. The to 3% of adult brain tumors (Wolf et al., 1993; Hakim et dysembryoplastic neuroepithelial tumor is characterized al., 1997), and about 10% of those occurring in children by the presence of multiple cortical nodules made up of (Chintagumpala et al. , 1996). This group encompasses small, oligo-li ke cells and a myxoid pattern rich in the ganglioneuroma, the gangliocytoma, the mucopolysaccharides. Mature neuronal cells are ganglioglioma, the desmoplastic ganglioglioma, the frequently detected throughout the tumor. Most of them ganglioneuroblastoma, the neurocytoma and are associated with microhamartias in the adjacent brain dysembryoplastic neuroepithelial tumors, in addition to a and pharmacoresistant epilepsy. The excellent prognosis series of lesions or tumors of a presumably of the majority of these tumors and the potential for hamartomatous nature. Other tumors that may be malignant transformation of the glial component in the histogenetically related are the pleomorphic ganglioglioma are the two mo t remarkable findings. xanthoastrocytoma, which presents neuronal Histological signs of anaplasia and greater mitotic and differentiation, and tumors associated with proliferative activities are associated w ith local neurofibromatosis. They are mostly located at the recurrences. Atypical neurocytomas occur o n ly supratentorial level, follow a benign course, and are exceptionall y. Treatme nt choice a re s urgical associated with a long history of drug-resistant epilepsy resectioning and, in those cases presenting greater (Fingarell a-Branger et aI. , 1992; Armstrong, 1993; proliferative activity and cytological atypia, Dauma -Duport, 1993; Wolf et al., 1993, 1994; postoperative radiotherapy may be recommended. Chintangupala et aI. , 1996; Hakim et al., 1997). These This paper reviews this heterogeneous group of lesions are often detected during the first decades of life, neoplasms and hamartomatous lesions, pointing out although they have been reported to occur at any age. presumable transitions among the different types of The mean 5-year survival is over 80% in the majority of mixed neuronal and glial brain tumors. A single term of the series described in the literature (Schild et al., 1997). "mixed neuronal-glial tumors" is defended, Epilepsy is relatively frequently associated with di tinguishing different subgroups of tumors, depending brain tumors (Ketz, 1974; Morris and Estes, 1993). on the predominant cell ular component. However, tumors mayor may not cau e epilepsy, even when they are of the same type and located in the same Key words: Hamartias, Gangliogliomas, Gl ioneuronal, brain area. T hus, tumors are not intrinsically Epilepsy epileptogenic. Furthermore, seizure activity associated with brain tumors may develop re latively soon or after several years (Ketz, 1974; Spencer et al., 1984; Morrel, 1989; Morris and Estes, 1993). Therefore, it is thought that in the peritumoral cortex occurs a series of changes that eventually may lead to epilepsy occurs. Offprint requests to: Dr. Santiago Ram6n y Cajal, MD , Ph .D. , Detailed microanatomical and neurochemical studies Departamento de Patologia, Clinica Puerta de Hierro, cl San Martin de of the peritumoral cortex temporal lobe epileptic patients Porres 4., 28035 Madrid, Spain. Fax: 34-91-3730535. e-mail: sramon@ presenting a variety of tumors have hown a decrease hpth.insalud.es inhibitory GABAergic interneurons (Haglu nd et aI., Mixed glioneuronal tumors

1992; Marco et al., 1996, 1997). Among the inhibitory and may involve the subarachnoid space. The pediatric intemeurons that are lost, chandelier cells appear to be desmoplastic ganglioglioma is typically identified as a, one of the most affected neurons (Marco et al., 1996, massive tumor, while the dysembryoplastic tumor is 1997). Since chandelier cell axons are virtually the only small, barely measuring a few millimeters, and source of inhibitory synapses on pyramidal cell axon circumscribed, corresponding to multiple superficial initial segments, and this region of the pyramidal cell cortical nodules of 0.5 to 3 mm in diameter (Ng et al., appears to be strategically important for the control of 1990; Daumas-Duport, 1993). Hamartias are usually pyramidal cell excitability, chandelier cells are microscopic lesions, and hamartomas can measure considered to be the most powerful cortical inhibitory several mm (Wolf et al., 1994). interneuron (De Felipe, 1999). On the other hand, At the histological level, this group of tumors is pyramidal cells are the main source of cortical efferent basically made up of: (a) mature gangliocytic neuronal axons and of intracortical collaterals and, consequently, cells with abundant cytoplasm, vesicular nuclei and they are responsible for the spread of epileptiform prominent nucleoli, usually arranged in groups, and activity. Thus, the loss of chandelier cells has been scattered binucleated neurons are often present; (b) suggested to play a crucial role in the development of small, mature neuronal cells, with or without projections, epilepsy (De Felipe, 1999). with a small amount of pale or slightly eosinophilic cytoplasm; (c) astrocytic and oligodendroglial glial cells; General histological features (d) lymphocytes at the perivascular level; (e) fibrillar stroma, similar to the neuropil, in those lesions Although most of these lesions or tumors are located presenting a neuronal component; (f) loose, myxoid in the temporal lobe, they have been detected throughout stroma with occasional cysts, a characteristic of the the neuroaxis, including the spinal cord. Macro- dysembryoplastic neuroepithelial tumors; (g) scopically, ganglionic tumors can be solitary or multiple, cytoarchitectural changes in the adjacent cortex, with solid or cystic. They are usual1 well circumscribed and neuronal, dysgenetic clusters (abnormal numbers and the diameter varies. Generally, they present calcifications arrangements of neurons); (h) conspicuous eosinophilic

Flg. 1. a. Gtbnwmnal hamarrks. leeion k mposed of ckwrnscribed rnicroscopic amregates of dborganlzed rnature neuronal and glial elernmw. b. An =ea of oortex with mwited cMtlcel dbwgankatlon, gliosk, neuronal loss and rnicrocalclfscaüons. Hematoxylin-eosin,x 250 Mixed glioneuronal tumors protein droplets and spherical structures known as (Wolf et al., 1995). Regional neuronal markers, such as granular bodies; and (i) calcifications. calbindin D-28K, expressed in Purkinje cells, can be detected in those tumors arising in the cerebelium. Ultrastructural and immunophenotypic features Description of the different leslons Light microscope studies of these tumors must frequently be complemented by ultrastructural and The hamartoma is defined as a mass of disorganized, immunohistochemical studies to determine the tumor but mature, neurons and glial celis; despite its tumor-like phenotype. The ultrastructural characteristics of neuronal gross appearance, it has no histological features of cells include dense core granules, cell processes with malignancy and no proliferative activity is observed. The microtubules and synapses associated with clear glioneuronal harnartias are poorly circumscribed lesions vesicles. Astrocyte cells contain abundant intermediate with misplaced neuronal cells (Fig. la). They include filaments. areas of dysgenesis (foca1 cortical dysplasia, with groups According to immunophenotypic analysis, the of large bizarre neurons accompanied by glial cells neuronal component expresses markers for a particular throughout the cortex) and rnicrodysgenesis in the form of cellular strain, as well as neurofilaments (NFP-H/m heterotopias, neuronal clustering and rows of perivascular epitopes), synaptophysin, class 111 beta-tubulin, MAP 2 giial cells (Fig. lb) (Volk and Prayson, 1997). and some neuropeptides (neuropeptide Y, met- The ganglioneuroma is composed exclusively of enkephalin, beta-endorphin, substance P, somatostatin, gangliocytic cells with occasional Schwann ceíls. Most etc) in almost 100% of cases (chromogranin A in 80% to frequently, it arises in association with the autonomous 90% of tumors); it also expresses the adhesion molecule and peripheral nervous systems; the exceptions, reported E-NCAM, an embryonic form of the neuronal cell in the central neuroaxis, are associated with ectopic adhesion molecule, which is positive in many dysplastic peripheral neural tissue or peripheral nerve rmts (Lantos neurons, in glioneuronal hamartias and in central et al., 1997). neurocytoma. Conversely, the cells in dysembryoplastic The gangliocytoma represents less than 0.5% of neuroepithelial tumors are mostly negative for E-NCAM brain tumors (Russell and Rubinstein, 1989). And is

Flg. 2. Qangliogliomas. a. An exarnple of ganglioglioma wkh a disecell growth pattern and the characteristic vascular arborlzation. b. An exmple of desmoplastic ganglioglioma with neurons enmeshed In a wllagemnrs, retlculin-rich stroma. Hematoxylin-dn, x 350 Mixed glioneuronal tumors composed of neuron-gangliocytic cells and a variable different portions of the lesion. It frequently assumes an component of non-neoplastic astrocytes. In contrast to alveolar arrangement, with a tree of narrow capillary the ganglioglioma, it has a less common cystic vessels (Fig. 2a), and clustered neuronal cells that tend component. Neurons usually have pleomorphism and to present more mature forms in the central area (Figs. bizarre forms. The hamartomatous or neoplastic nature 3a,b). Occasionally, there is a prominent desmoplastic of this lesion has been questioned (Lantos et al., 1997). reaction with abundant vessels both in the leptomeninges Tumor recurrence after complete removal has been and at the cortical leve1 (Fig. 2b) or tumors with a reported (Felix et al., 1994). predominant gangliocytic component (Fig. 4a). The glial The ganglioglioma is a tumor with a mixed glial and component shows a variable cell density with areas neuronal components (Figs. 2,3). It is the most common similar to the common glial tumor, especially that of the of the glioneuronal neoplasms, with an incidence pilocytic astrocytoma. Recently, a distinctive ranging between 0.4% and 6.25% of primary brain glioneuronal tumor with neuropil-like islands has been tumors (Russell and Rubistein, 1989; Chintagumpala et described (Fig. 4b). These islands were composed of al., 1996; Isimbaldi et al., 1996; Hakim et al., 1997; oligodendrocyte-like elements "neurocytic" and well Lantos et al., 1997). It is generally located in the differentiated neurons (Teo et al., 1999). The temporal lobe, although it has been observed in frontal ganglioglioma has anaplastic and malignant variants lobe and at other sites. The mean patient age at diagnosis (Sasaki et al., 1996; Hakim et al., 1997). Moreover, is 20 years, ranging from 1 to 80 years. There is a slight composite pleomorphic xanthoastrocitoma (PXA) and male predilection (Ng et al., 1990; Wolf et al., 1994; ganglioglioma have been described (Perry et al., 1997). Chintagumpala et al., 1996; Isimbaldi et al., 1996; These authors describe three forms of association Hakim et al., 1997). The macroscopic aspect is generally between PXA and GG, with some tumors displaying cystic with a wall nodule. Microscopic study discloses a both neoplastic elements with minimal intermingling, heterogeneous lesion, with different histological cell- others showing features of typical PXA with dysmorphic growth patterns. The architectural pattern of this tumor ganglion cells which express synaptophisin (SYN) varies from one case to another and even among the immunoreactivity, and others presenting a composite of Mixed glioneuronal tumors

PXA and GG arranged as in a "collision tumor". We Raymond et al., 1995; Pasquier et al., 1996). It is have also observed tumors composed predominantly of characterized by the presence of multiple cortical typical GG but with abundant multinucleated cells nodules varying in diameter, with a gelatinous dispersed among the glial and neuronal celis. These cells consistency and distended cortical ribbon. It is made up are immunoreactive for SYN and Glial Fibrilar Acidic of small, oligo-like cells with scarce cytoplasm and a Protein (GFAP) and in some areas were associated with myxoid pattern rich in mucopolysaccharides (Fig. 7). a desmoplastic stroma or a pilocitic component of the Mature neuronal cells are frequently detected throughout GG. Those areas could represent incipient PXA (Fig. 5) the tumor (Armstrong, 1993; Daumas-Duport, 1993; arising in otherwise typical GG. Hirose et al., 1994). This lesion is also easily confused The neurocytoma represents approximately 0.5% of with the low-grade oligodendroglioma and astrocytoma intracranial tumors (Kim et al., 1997); the usual location and frequently there is adjacent cortical migration is intraventricular, near the foramen of Monro. Most alterations. patients show symptoms of intracranial hypertension and The presence of satellites in the adjacent cortex the clinical history is usually short. This lesion is should be assessed an immunohistochemical study composed of small, mature neurons, fibrillar stroma and carried out to detect the neuronal component (Daumas- frequent calcifications (Fig. 6). It is easily confused with Duport, 1993; Hirose et al., 1994). In contrast to the oligodendroglioma. It presents no cytological atypias hamartias, the cellular elements do not express E-NCAM or significant mitotic activity (Fingerella-Branger et al., immunoreactivity (Wolf et al., 1995). 1992; Nishio et al., 1992; Tsuchida et al., 1996; Lantos Another malformative hamartomatous lesion that et al., 1997). The existence of an extraventricular has a neuronal component is the so-called meningo- neoplasm with the features of the neurocytoma has angiomatosis, which may present a cytological recently been reported (Giangaspero et al., 1997). component comparable to that of the gangliocytoma. It The dysembryoplastic neuroepithelial tumor is is characterized by its prominent vascular pattern and associated with chronic intractable seizure disorders and fibrosis in the leptomeninges, which is extended may represent up to 25% of al1 lesions removed to treat throughout the Virchow-Robin spaces (Fig. 8) (Goates et chronic drug-resistant epilepsy (Wolf et al., 1993, 1995; al., 1991; Prayson, 1995).

Flg. 4. Exarnples oí glioneuronal tumors with a predorninant component oí gangliooytlc cells (a) and a rossetold growth paltem @). Hernatoxyíin-eosin, x400 Mixed glioneuronal tumors

Most of these tumors or lesions arise within an findings in over 160 lesions associated with chronic underlying hamartomatous condition, including frequent epilepsy coincide with those of other studies involving dysplastic pathology in the adjacent cerebral cortex lesions associated with drug-resistance epilepsy (Wolf et (Wolf et al., 1995; Lantos et al., 1997). Moreover, our al., 1995; Alvarez et al., 1997) in suggesting presumable

Flg. 5. An example of an xanthoastrocitrna pleomorphic showing numerous giant cells and a cellular background of glial cells and vety sparse gangliocyiic-like cells. Hematoxylin-eosin, x 300

Flg. 6. Neurocytoma. The tumor is wmposed of small neurocytes in a fine fibrillar background. Hematoxylin-eosin, x400 Mixed glioneuronal tumors

transitions among the different types of neuronal brain and, exceptionally, in the neurocytoma (Mrak, 1994; tumors. In fact, we postulate that they may constitute a Yamamoto et al., 1996; Eng et al., 1997). Thus, it is single tumor group with different subtypes, depending important to identify this group of tumors, differentiating on the predominance of a mature or immature neuronal them from others with a more aggressive course that component, on the glial cellularity or on the may require chemotherapy andlor radiotherapy. They are accompanying fibrovascular stromal reaction. This frequently confused with astrocytic glial tumors, with unifying concept of glioneuronal tumors of the brain oligodendrogliomas and even with primary may explain recent reports concerning transitibnal forms neuroectodermal tumors. Nevertheless, low-grade of neuronal brain tumors and the divergent astrocytic tumors have been obsewed in association with differentiation of these lesions (Powell et al., 1996; chronic epilepsy and, recently, a distinctive group of Yamamoto et al., 1996; Shimbo et al., 1997). In this astrocytic tumors has been reported to be associated with context, there are some reports of tumors presenting long-term epilepsy, with an excellent prognosis features of the dysembryoplastic neuroepithelial tumor (Bartolomei et al., 1997). and the ganglioglioma (Shimbo et al., 1997), as well as of the neurocytoma and the gangliocytoma (Yamamoto a) Biological criteria et al., 1996) and other combinations. The location of the tumor itself is a prognostic factor Prognostic criteria related to its suitability for resection, which is the chosen treatment. Even the childhood desmoplastic Most of the tumors or lesions associated to refractary ganglioglioma, which is detected before the child epilepsi and presenting a neuronal component have an reaches the age of two and is very large in size, can have excellent prognosis, with a low incidence of recurrence a favorable outcome if completely removed andlor of malignant transformation. Such malignant (VandenBerg et al., 1987; Ng et al., 1990). The detection transformation has been reported in up to 3% of of a neurocytoma or ganglioglioma in a patient over 50 gangliogliomas (Sasaki et al., 1996; Hakim et al., 1997) years of age is associated with a worse prognosis

Flg. 7. a and b. Dysembryoplastic neuroepithelial tumor. The intracortical riodules show a mixed population of glial and neuronal cells, with mícmcysts and a frequent target-like pattem. Hematoxylin-eosin a, x150; b, x 400 Mixed glioneuronal tumors

(Prayson et al., 1995). Likewise, the ganglioglioma that according to conventional criteria for glial tumors. does not develop within the setting of chronic intractable Among the gangliogliomas, there are recurrent and epilepsy has a short duration and may have a more anaplastic tumors, with nuclear and cytological atypia at aggressive clinical behavior (Prayson et al., 1995). the leve1 of the astrocytic component (Kaba et al., 1996; Some tumors may be associated with specific Sasaki et al., 1996; Hakim et al., 1997). Likewise, an phakomatoses or inheritable diseases (Lantos et al., increase in the proliferative activity of the glial cells 1997). The ganglioglioma is not associated with any with specific markers, such as Ki67 (MIBl), is detected specific phakomatosis, but it is associated with neuronal (Hirose et al., 1997). These histological signs are migration disorders (in up to 30% of cases) and with observed in up to 10% of gangliogliomas, appearing Down's syndrome, orofaciodigital synostosis and other both in the initial biopsy and in the recurrent lesions, and congenital disorders (in about 5% of cases). In contrast, they are associated with a worse prognosis (Hakim et al., the gangliocytoma is associated with Cowden's disease 1997). In fact, the 1993 WHO classification identified and the ganglioneuroma with the familia1 tumor three grades of ganglioglioma on the basis of cellularity, syndrome (Lantos et al., 1997). cytological atypias, the presence of necrosis, and vascular proliferation. Grade 1 corresponds to the well- b) Histological criteria differentiated tumor; grade 11 includes the ganglioglioma having increased cellularity and nuclear pleomorphism; In this group of tumors having a mixed neuronal and and grade 111, those presenting necrosis, numerous neuronal-glial component, the cytological characteristics mitoses and abundant vascular proliferation. There is a of the neurons and of the glia must be assessed clear correlation between the cytological degree and separately. The neurons may have dysplastic features, proliferative activity of a ganglioglioma and the nuclear atypia and abnormal fonns, which should not be prognosis (Wolf et al., 1994). interpreted as signs of malignancy, but as degenerative Exceptional cases have been reported of atypical changes. The glial component, which sometimes neurocytoma, with histological evidence of atypia and undergoes malignant transformation, must be assessed necrosis and proliferative indices that also correlated

Fig. 8. Meningoangiomatosis. a. The lesion shows areas of the cortex withI abundant microcalcifications. b. A striking fibrosis throughout the Virchow- Robin spaces and a mixed gliolieuronal csll population. Hematoxyiin-eosinx 150 Mixed glioneuronal tumors with patient survival (Mrark, 1994; Fujimaki et al., completely resected and in 50% to 70% of cases of 1997). A few cases of craniospinal dissemination of partial resection. In the latter cases, subsequent central neurocytoma have been documented (Eng et al., radiotherapy prevented recurrence in up to 100% of 1997). It is interesting that some series show an cases, according to some authors (Fujimaki et al., 1997; incidence of anavlastic transformation in uv to 12% of Perry et al., 1997) with a 5-year survival rate of 88% pleomorphic xa~thoastrocytomas(Fig. 5) (perry et al., (Nisio et al., 1992; Isimbaldi et al., 1996). 1997). In dysembryoplastic neuroepithelial tumors, given Óther classical histological features to be assessed the excellent clinical prognosis and the fact that include the interface between the tumor and the adjacent recurrence has not been recorded, radiotherapy and parenchyma, which is usually clear and the extension of chemotherapy are not indicated (Raymond et al., the tumor to the leptomeninges and the subarachnoid 1995). spaces which, in contrast to other brain tumors, is not always associated with a worse prognosis (VandenBerg Acknowledgements. We thank Eloy Blanco for his assistance with the et al., 1987; Wolf et al., 1993, 1995; Chintagumpala et photographs and Steven Jones for preparing the manuscript. This work al., 1996). Two cases of leptomeningeal dissemination was supported by grants from the 'Fondo de Investigaciones Sanitarias showing no cytological evidence of malignity have del Ministerio de Sanidad de Espatia", FlSS 9612174, 9910504 and the recently been reported (Yamamoto et al., 1996; Eng et SANCA Foundation. al., 1997). c) Immunophenotypic and molecular criteria References

For the correct diagnosis of these lesions, the Alvarez L.A., Duchowny M.S., Jayakar P., Ha~eyA.S., Resnick T.J., assessment of neuronal and glial differentiation markers Dean P., Yaylali l. and Bruce J. (1997). Neuropathology of refractoty is usually necessary. It is essential to reflect the epilepsy in children. Rev. Neurol. 25, 757-759. proliferative activity, since it may be of prognostic Armstrong D.D. (1993). The neuropathology of temporal lobe epilepsy. significance in some types of tumors. In fact, in the J. Neuropathol. Exp. Neurol. 52,433-443. ganglioglioma (Hirose et al., 1994; Alvarez et al., 1997). Bartolomei J.C., Christopher S., Vives K., Spencer D.D. and Piepmeier and the central neurocytoma (Yamamoto et al., 1996), J.M. (1997). Low-grade gliomas of chronic epilepsy: a distinct clinical the percentage of cells positive for Ki67/MIB1 correlates and pathological entity. J. Neurooncol. 34,79-84. with the probability of local recurrences. However, it is Chintagumpala M.M., Armstrong D, Miki S., Nelson T., Cheek W., important to note that other neuronal tumors, such as the Laurent J., Woo S.Y. and Mahoney D.H. Jr. (1996). Mixed neuronal- dysembryoplastic neuroepithelial tumor, may show a glil tumors (gangliomas in children). Pediatr. Neurosurg. 24, 306- high MIBl labeling index, but this does not indicate a 313. worse prognosis (Daumas-Duport, 1993). Daumas-Duport C. (1993). Dysembryoplastic neuroepithelial tumours. The expression of oncogenic proteins such as p53 Brain Pathol. 3,283-295. has been detected in some gangliogliomas, and this may De Felipe J. (1999). Chandelier cells and epilepsy. Brain 122, 1807- be an indicator of a worse prognosis and a tendency to 1822. recur (Hirose et al., 1994). Other markers associated Eng D.Y., DeMonte F., Ginsberg L., Fuller G.N. and JaecMe K. (1997). with a worse prognosis in primitive neuroectodermal Craniospinal dissemination of central neurocytoma. Report of two tumors, such as N-myc amplification, are absent or do cases. J. Neurosurg. 86,547-552. not indicate a worse prognosis in neuronal tumors. Felix Y., Bilbao J.M., Asa S.L., Tyndel F., Kovacs K. and Becker L.E. Immunoreactivity with E-NCAM may be useful in (1994). Cerebral and cerebellar gangliocytomas: a morphological distinguishing hamartias from dysembryoplastic study of nine cases. Acta Neuropathol. 88.246-251. neuroepithelial tumors. Fingarella-Branger D., Pellissier J.F., Daumas-Duport C., Delisle M.B., Pasquier B., Parent M., Gambarelli D., Rougon G. and Hassoun J. Treatment (1992). Central neurocytomas. Critica1 evaluation of a small-cell neuronal tumor. Am. J. Surg. Pathol. 16,97-109. The treatment chosen in al1 these tumors is surgical Fujimaki T., Matsuno A., Sasaki T., Toyoda T., Matsuura R., Ogai M., resection. The 5-year survival rate is over 80%. In the Kitanaka C., Asai A,, Matsutani M. and Kirino T. (1997). Prolirative ganglioglioma, surgical excision is curative. activity of central neurocytoma: measurement of tumor volume Radiotherapy is of questionable utility in grade 11 lesions doubling time, MIB-1 staining index and bromodeoxyuridine labeling and is recommended in those classified as grade 111, index. J. Neurooncol. 32, 103-109. given the greater probability of recurrence. It is also Giangaspero F., Cenacchi G., Losi L., Cerasoli S., Bisceglia M. and advisable in those cases in which resection was not Burger P.C. (1997). Extraventricular neoplasms with neurocytoma complete (Wolf et al., 1994; Hakim et al., 1997). It is features. A clinicopathological study of 11 cases. Am. J. Surg. interesting to note that remission in a case of grade 111 Pathol. 21, 206-212. gangliogliorna treated with cis-retinoic acid (Perry et al., Goates J.J., Dickson D.W. and Horoupian D.S. (1991). Meningio- 1997) has been reported. angiomatosis: an immunocytochemicalstudy. Acta Neuropathol. 82. In the central neurocytoma, local recurrences are 527-532. absent in 100% of cases in which the tumor was Haglund M.M., Berger M.S., Kunkel D.D., Franck J.E., Ghatan S. and Mixed glioneuronal tumors

Ojemann G.A. (1992). Changes in gamma-aminobutyric acid and Prayson R.A., Khajavi K. and Comair Y.G. (1995). Coriical archiectural somatostatin in epileptic cortex associated with low-grade gliomas. abnorrnalities and MlBl immunoreactivity in gangliogliomas: a study J. Neurosurg. 77,20821 6. d 60 patients with intracranial tumors. J. Neuropathol. Exp. Neurol. Hakim R., Loeffler J.S., Anthony D.C. and Black P.M. (1997). 54,513-520. Gangliomas in aduls. Cancer 79, 127-131. Raymond A.A., Fish D.R., Sisodiya S.M., Alsanjari N., Stevens J.M. and Hirose T., Scheithauer B.W., Lopes M.B. and VandenBerg S.R. (1994). S~ONO~S.D. (1995). Abnormalities of gyration, heterotopias, Dysembryoplastic neuroepithelial tumor (DNT): an immuno- tuberous sclerosis, focal cortical dysplasia, microdysgenesis, histochemical and ultrastructural study. J. Neuropathol. Exp. Neurol. dysembryoplastic neuroepithelial turnour and dysgenesis of the 53, 184-195. archicortex in epilepsy. Clinical, EEG and neuroimaging features in Hirose T., Schneithauer B.W., Lopes M.B., Gerber H.A., Altermatt H.J. 100 adult patients. Brain 118, 629-660. and VandenBerg S.R. (1997). Ganglioglioma: an ultrastructural and Russeil D.S. and Rubinstein L.J. (1989). In: Pathology of tumors of the immunohistochemical study. Cancer 79,989-1003. nervous system. 5th ed. Russell D.S. and Rubinstein L.J. (eds). lsimbaldi G., Sironi M., Tonnarelli G.P., Roncoroni M., Declich P. and Edward Arnold. London. pp 289-306. Galli C. (1996). Ganglioglioma: a clinical and pathologicai study of Sasaki A., Hirato J., Nakazato Y., Tamura M. and Kadowaki H. (1996). 12 cases. Clin. Neuropathol. 15, 192-199. Recurrent anaplastic ganglioma: pathological characterization of Kaba S.E., Langford L.A., Yung W.K. and Kyritsis A.P. (1996). tumor cells. Case report. J. Neurosurg. 84, 1055-1059. Resolution of recurrent malignant ganglioglioma aíter treatment with Schild S.E., Scheithauer B.W., Haddock M.G., Schiff D., Burger P.C., cis-retinoic acid. J. Neuroonool. 30, 55-60. Wong W.W. and Lyoins M.K. (1997). Central neurocytomas. Cancer Ketz E. (1974). Brain tumors and epilepsy. In: Handbook of clinical 79, 790-795. neurology. Vol. 16. Vinken P.J. and Bruyn G.W. (eds). North- Shimbo Y., Takahashi H., Hayano M., Kumagai T. and Kameyana S. Holland. Amsterdam. pp 254-269. (1997). Temporal lobe lesion demonstrating features of Kim D.G., Park S.H., Kim I.H., Chi J.G., Jung H.W., Han D.H., Choi K.S. dysembryoplastic neuroepithelial and ganglioma: a transitional and Cho B.K. (1997). Central neurocytoma: the role of radiation form? Clin. Neuropathol. 16,65-68. therapy and long term outcome. Cancer 79,1995-2002. Spencer D.D., Spencer S.S., Mattson R.H. and Williarnson P.D. (1984). Lentos P.L., Vanderberg S.R. and Kleihues P. (1997). Tumours of the lntracerebral masses in patients with intractabie partial epilepsy. nervous system. In: Greenfileld's neuropathology. 6th ed. Graham Neurology 34, 432-436. D.I. and Lentos P.L (4s). Arnold. London. pp 654- 676. Teo J.G.C., Gultekin S.H., Bilsky M., Gutin P. and Rosenblum M.K.. Marco P., Sola R.G., Pulido P., Nijarde M.T., Sanchez A, Ramon y (1999). A disünctive glioneuronal tumor of the adult cerebrum with Cajal S. and DeFelipe J. (1996). lnhibitory neurons in the human neuropil-like (including "rosetted") islands. Am. J. Surg. Pathol. 23, epileptogenic temporal neocortex: An immunocytochemical study. 502-510. Brain 119, 1327-1348. Tsuchida T., Matsumoto M., Shirayama Y., lmahori T., Kasai H. and Marco P., Sola R.O., Ramon y Cajal S. and DeFelipe J. (1997). Loss of Kawamoto K. (1996). Neuronal and glial characteristics of central inhibitory synapses on the soma and axon lnitial segment of neurocytoma: electron microscopical anaiysis of two cases. Acta pyramidal cells in human epileptic peritumoural neocortex: Neuropathol. 91,573-577. irnplications for epilepsy. Brain Res. Bull. 44, 47-66. VandenBerg S.R., May E.E., Rubinstein L.J., Herman M.M., Perentes Morrell F. (1989). Varieties of human secondary epileptogenesis. J. Clin. E., Vinores S.A., Collins V.P. and Park T.S. (1987). Desmoplastic Neurophysiol. 6, 227-275. supratentorial neuroepithelial tumors of infancy with divergent Morris H.H. and Estes M.L (1993). Brain tumors and chronic epilepsy. diiíerentiation potential ("desmoplastic infantile gangliomas'). Report In: The treatment of epilepsy: principies and pracüce. Wyllie E. (ed). on 11 cases of a distinctive embryonal tumor with favorable Lea and Febiger. Philadelphia. pp 659-666. prognosis. J. Neurosurg. 66,58-71. Mrak R.E. (1994). Malignant neumytic tumor. Hum. Pathol. 25, 747- Volk E.E. and Prayson R.A. (1997). Hamartomas in the setting of 752. chronic epilepsy: a clinicopathologic study of 13 cases. Hum. Pathol. Ng T.H.K., Fung C.F. and Ma LT. (1990). The pathological spectrurn of 28,227-232. desmoplastic infantile gangliogliomas. Histopathology 16,235-241. Wolf H.K., Campos M.G., Zentner J., Hufnagel A., Schramm J., Elger Nishio S., Takeshita l., Kaneki Y. and Fukui M. (1992). Cerebral C.E. and Wiestler O.D. (1993). Surgical pathology of temporal lobe neurocytoma. A new subset of benign neuronal tumors of the epilepsy. Experience with 216 cases. J. Neuropathol. Exp. Neurol. cerebrum. Cancer 70,529-537. 52,499-506. Pasquier B., Bost F., Peoch'h M., Barnoud R. and Pasquier D. (1996). WoK H.K., Müller M.B., SpAnle M., Zentner J., Schramm J. and Wiestler Neuropathologic data in drug-resistant partial epilepsy. Report d a O.D. (1994). Ganglioglioma: a detailed histopathological and series of 195 cases. Ann. Pathol. 16, 174-181. immunohistochemical analysis of 61 cases. Acta Neuropathol. 88, Peny A., Giannini C., Scheithauer B.W., Rojiani A.M., Yachnis A.T., Seo 166-173. I.S., Johnson P.C., Kho J. and Shapiro S. (1997). Composite Wolf H.K., Wellmer J., Muller M.B., Wistier O.D., Hufngel A. and Pietsch pieomorphic xanthoastrocytoma and ganglioma: report of four cases T. (1995). Glioneuronal malformative lesions and dysembrioplastic and review of the literature. Arn. J.Surg. Pathol. 21,763-771. neuroepitelial tumors in patients with chronic pharmacoresistant Powell S.Z., Yachnis A.T., Rorke L.C., Rojiani A.M. and Eskin T.A.. epilepsie. J. Neropathol. Exp. Neurol. 5,245-254. (1996). Divergent dierentiation in pleomorphic xanthoastrocytoma. Yamamoto T., Komori T., Shibata N., Toyoda C. and Kobayashi M. Evidence for a neuronal element and possible relationship to a (1996). Multifocal neurocytoma/gangliocytoma with extensive ganglion cell tumors. Am. J. Surg. Pathol. 20, 80-85. leptomeningeal dissemination in the brain and spinal cord. Am. J. Prayson R.A. (1995). Meningioangiornatosis. A clinicopathologic study Surg. Pathol. 20, 363-370. including MlBl immunoreactivity. Arch. Pathol. Lab. Med. 119, 1061-1 064. Accepted December 21,2000