Cost of Migrat ion : Invas ion of Mal ignant Gl iomas and Impl icat ions for Treatment

Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies. J Clin Oncol 21:1624-1636. © 2003 by American Society of Clinical Oncology. INVASIVE PHENOTYPE OF MALIGNANT GLIOMAS: A CLINICAL CHALLENGE With the development of new technical adjuncts for surgical management of gliomas, such as neuronavigation, functional imaging, and cortical mapping, a renewed interest in a more radical surgical removal of these tumors has emerged, and it has been hypothesized that more complete resection of tumors may translate into prolonged survival. However, the inherent tendency of glial tumors to widely disseminate within normal brain has to be regarded as a natural limit to this concept. With the exception of benign ependymomas, the rare subependymomas, gangliocytomas, dysembryoplastic neuroectodermal tumors, subependymal giantcell astrocytomas, and some nodular pilocytic astrocytomas, all other glial tumors are invasive. The degree of invasiveness does not necessarily correlate with the grade of malignancy. Low-grade astrocytomas often show extensive infiltration of normal brain, which limits surgical resection and eventually leads to recurrence and progression of the disease. The invasion of high-grade gliomas follows similar anatomic structures, but the dynamics of this process seem to be more rapid. After surgical removal of a malignant glioma, invariably a recurrent tumor will manifest; in more than 95% of the cases, the tumor will manifest within 2 to 3 centimeters of the resection cavity, and frequently immediately adjacent to the resection cavity (Fig 1). Distant satellite lesions several centimeters away from the site of the initial presentation may also be found. These lesions may also occur in the contralateral hemisphere and may increasingly become apparent in the presence of a controlled primary site as documented for recent experimental local treatments. These types of multifocal lesions have been reported to represent 1% to 10% of cases at the initial presentation, with a significantly higher incidence in later stages of the disease. Many of these tumors may not be truly multifocal but rather may reflect manifestations of more rapidly proliferating foci within a larger area of microscopically invaded brain (Fig 2). The dissemination of malignant gliomas has been investigated extensively in the past. Analyzing a series of 120 untreated gliomas, Scherer demonstrated 60 years ago that most glial tumors show an infiltrative growth pattern. The invasion of normal brain by malignant brain tumors was found to be associated with distinct anatomic structures following myelinated axons, the basement membranes of blood vessels or other basement membrane–like structures, and the subependyma. It was noted that, because of a high affinity to myelinated fiber tracts, invasive tumor cells could be found several centimeters away from the bulk lesion, sometimes with extensions into the contralateral hemisphere. INVASIVE PHENOTYPE: EARLY RECOGNITION AND SURGICAL COST This infiltrative biologic behavior was recognized early by neurosurgeons. In the 1920s, Walter E. Dandy performed a hemispherectomy for a “tumor, which was clearly of the infilFrom the Department of Neurosurgery, University Hospital Lübeck, Lübeck; Department of Neurosurgery, University Hospital Hamburg, Hamburg, Germany; Department of Anatomy and Cell Biology, University of Bergen, Bergen, Norway; and Barrow Neurological Institute, St Joseph’s Hospital, Phoenix, AZ. Submitted May 8, 2002; accepted January 27, 2003. Supported by grants Gi 218/2-2 Gi 218/2-4 from the Deutsche Forschungsgemeinschaft. Address reprint requests to Alf Giese, MD, Department of Neurosurgery, University Hospital Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; email: alf.giese@neurochirurgie.mu-luebeck.de. © 2003 by American Society of Clinical Oncology. 0732-183X/03/2108-1624/$20.0