Multifocal Glioblastoma (WHO Grade IV) Pieter Wesseling, MD, PhD Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands

Clinical History and Radiology A 63-year-old woman presented with a history of disturbed ocular motility and nausea. T1 weighted MR images with contrast revealed multiple, contrast-enhancing intracerebral lesions (corpus callosum, left frontal lobe, left cerebellar peduncle and hemisphere; see below). A needle biopsy was taken of the lesion in the corpus callosum. Review of the MR flare images suggested a connection between the different lesions via white matter tracts. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Histopathological Features The small biopsy fragments show a highly cellular glial tumor. The tumor cells generally have astrocytic features with eosinophilic cytoplasm and cell processes. There is moderate to marked nuclear pleiomorphism and mitoses are readily found. Occasionally round nuclei with clear perinuclear halo's can be identified, but this was found to be insufficient for recognition of an oligodendroglial component. Dispersed florid microvascular proliferation and areas of necrosis (focally surrounded by pseudopallisading of tumor cell nuclei) are present. Histopathological diagnosis: Glioblastoma multiforme. Multifocal and multicentric gliomas The differential diagnosis of multiple lesions in the central nervous system includes metastases, infectious/inflammatory diseases, demyelinating disorders, vascular diseases, malignant lymphoma, but also glioma. Multiple gliomas can occur as synchronous (diagnosed at initial presentation) and metachronous (appearing some time after initial diagnosis) lesions [1]. Metachronous dissemination of gliomas may well be increasing as patients live longer [2]. Only a small percentage of glioma patients (estimated by some authors as 2%) show multiple, seemingly independent lesions at initial presentation [3, 4]. Glioblastomas relatively frequently present as multiple synchronous lesions [5]. This finding may be explained by the relatively high incidence [6] and by the aggressive biological behavior of this type of glioma. In the literature, multiple gliomas are often designated as multifocal or multicentric lesions [3, 5]. Multifocal gliomas are considered to be the result of dissemination of glioma cells via cerebrospinal fluid pathways, meninges, or white matter tracts, while multicentric gliomas are widely separated lesions that can not be attributed to the pathways just mentioned. The distinction between multifocal and multicentric gliomas is, however, not straight forward. It has been suggested that supra- and infratentorial co-occurrence of multiple gliomas indicates true multicentricity [7]. However, a recent study suggests that migration of glioma cells may very well occur via cerebro-cerebellar white matter tracts [8]. In some studies, classification of gliomas as multicentric is based on histopathological differences between the different lesions. Gliomas are, however, often heterogeneous with marked spatial differences in cellular phenotype and malignancy grade. Since molecular genetic studies demonstrated a common origin in such different components, these heterogeneous gliomas are considered as clonal lesions [9, 10]. Moreover, a post mortem study using whole brain sections showed that multifocal glioblastomas can emerge in the background of a better differentiated astrocytic neoplasm [11]. More recently, the occurrence of cerebellar glioblastoma was described to arise in a patient with supra- and infratentorial gliomatosis cerebri [12]. One study reported that using MRI, CT, or both, only in 12 of the 26 patients with multiple foci of glioma at initial diagnosis various patterns of spread were evident or suggested (subarachnoid > intraventricular > direct brain penetration) [13]. However, glioma cells can migrate (sometimes over long distances) via white matter tracts with relative preservation of the original tissue architecture. Conventional radiological techniques tend to underestimate the extend of such diffuse infiltrative growth, especially when the blood-brain barrier is still intact and, consequently, contrast-enhancement is absent. In this setting, multifocal malignant progression may radiologically result in multiple contrast-enhancing lesions and falsely suggest the presence of multiple independent lesions. The best way to prove that "multicentric" gliomas are indeed polyclonal is by showing an independent origin of the different lesions [14]. One study performing genetic analysis of multifocal glioblastoma multiforme indicated a monoclonal origin [15]. Recent studies suggest that the multifocality of gliomas as detected by radiological investigations implies worse prognosis [16, 17]. The management of patients with multifocal or multicentric glioma is controversial. Some authors advocate and others reject an aggressive surgical approach [5]. The benefit of the newer generation of chemotherapeutics and of targeted therapy is not yet clear. Take home message Gliomas in adults often show diffuse (sometimes extremely diffuse) infiltration in the neuropil; can be heterogeneous lesions; occasionally present as multiple lesions in the CNS. References Lafitte F, Morel-Precetti S, Martin-Duverneuil N, Guermazi A, Brunet E, Heran F, Chiras J. Multiple glioblastomas: CT and MR features. Eur Radiol (2001) 11:131-136. Buhl R, Barth H, Hugo H-H, Hutzelmann A, Mehdorn HM. Spinal drop metastases in recurrent glioblastoma multiforme. Acta Neurochir (Wien) (1998) 140:1001-1005. Batzdorf U, Malamud U. The problem of multicentric gliomas. J Neurosurg (1963) 20:122-136. Barnard RO, Geddes JF. The incidence of multifocal cerebral gliomas. A histologic study of large hemisphere sections. Cancer (1987) 60:1519-1531. Salvati M, Caroli E, Orlando ER, Frati A, Artizzu S, Ferrante L. Multicentric glioma: Our experience in 25 patients and critical review of the literature. Neurosurg Rev (2003) 26:275-279. CBTRUS Statistical Report. Primary Brain Tumors in the United States, 1998-2002 (2006). Central Brain Tumor Registry fo the United States (www.cbtrus.org). Salvati M, Oppido PA, Artizzu S, Fiorenza F, Puzzilli F, Orlando ER. Multicentric gliomas. Report of seven cases. Tumori (1991) 77:518-522. Roth J, Nass D, Ram Z. Cerebellar tumor extension as a late event of long standing, supratentorial low grade gliomas: Case Report. Neurosurgery (2006) 58:1210-1211. Berkman RA, Clark WC, Saxena A, Robertson JT, Oldfield EH, Ali IU. Clonal composition of glioblastoma multiforme. J Neurosurg (1992) 77:432-437. Kraus JA, Koopman J, Kaskel P, Maintz D, Brandner S, Schramm J, Louis DN, Wiestler OD, von Deimling A. Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol (1995) 54:91-95. Burger PC, Kleihues P. Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies. Cancer (1989) 63:2014-2023. Senatus PB, McClelland S, Tanji K, Khandji A, Huang J, Feldstein N. The transformation of pediatric gliomastosis to cerebellar glioblastoma multiforme presenting as supra- and infratentorial acute disseminated encephalomyelitis. Case report. J Neurosurg (2005) 102:72-77. Kyritsis AP, Levin AV, Yung WK, Leeds NE. Imaging patterns of multifocal gliomas. Eur J Radiol (1993) 16:163-170. Kleihues P, Cavenee W, eds. World Health Organization classification of tumours. Pathology and Genetics: Tumours of the Nervous System (2nd ed). Lyon: IARC Press, 2000. Krex D, Mohr B, Appelt H, Schackert HK, Schackert G. Genetic analysis of a multifocal glioblastoma multiforme: A suitable tool to gain new aspects in glioma development. Neurosurg (2003) 53:1377-1384. Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF. MR imaging correlates of survival in patients with high-grade gliomas. Am J Neuroradiol (2005) 26:2466-2474. Parsa AT, Wachhorst S, Lamborn KR, Prados MD, McDermott MW, Berger MS, Chang SM. Prognostic significance of intracranial dissemination of glioblastoma multiforme in adults. J Neurosurg (2005) 102:622-628.