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