In this paper, we report a case of multifocal and multicentric supratentorial and infratentorial GBM in an adult. Our review of the pertinent literature revealed that only 11 other cases of concomitant supratentorial and infratentorial GBM have been documented. The clinical findings in all published adult cases of supratentorial and infratentorial GBM are summarized in . The age at diagnosis ranged from 24 to 74 years (median 51.5 years). Ten patients were male and two were female. Infratentorial tumors occurred in the cerebellar hemisphere (5 cases), vermis (3 cases), brainstem (3 cases), and cerebellopontine angle (1 case). Histopathological analysis of the supratentorial and infratentorial masses matched in 9 cases and was mixed in 3 cases. In this series, spanning 5 decades with varying management strategies, overall survival ranged from 2 to 18 months (median 4 months).
Literature review of studies on concomitant supratentorial and infratentorial glioblastomas in adults*.
Previously, multifocal and multicentric GBM have been associated with a worse prognosis than solitary GBM, with median patient survival estimates of 6–8 months after different treatment modalities [13
]. A recent study found a statistically significant difference in median survival between patients with multifocal GBM and solitary GBM of 9.6 months versus 14.6 months (P
= 0.014) but not between patients with multicentric GBM and solitary GBM (12.9 months and 14.6 months, resp.) [15
]. Tumor dissemination at the time of diagnosis can also serve as a prognostic marker. One study stratified patients into three groups based on solitary or multifocal tumors and whether there was subependymal or subarachnoid dissemination at the time of diagnosis [16
]. Patients with multifocal tumors and subependymal and subarachnoid dissemination had shorter progression free and overall survival than patients with solitary tumors with subependymal and subarachnoid dissemination. However, patients with multifocal tumors without subependymal and subarachnoid dissemination had similar outcomes to patients with solitary GBM.
The radiographic appearance of multifocal and multicentric GBM is indistinct from that of metastases, with MR imaging displaying multiple contrast-enhancing masses [3
]. Certain MR imaging features such as variable lesion morphology, mild peritumoral edema, and irregular tumor margins can suggest the diagnosis of multiple or multicentric GBM [15
]. Since metastasis from extracranial primary tumors is the most common diagnosis associated with multiple brain masses and the most common intra-axial posterior fossa tumor in adults, histopathological verification is imperative before making a diagnosis of metastasis, especially in patients with no known primary neoplasm [3
The diagnostic workup for multifocal and multicentric GBM is generally the same as that for solitary GBM. Dissemination of GBM, however, can occur intracranially or throughout the spinal axis [16
]. In such cases of GBM with leptomeningeal gliomatosis, either suspected clinically or radiographically due to the presence of leptomeningeal enhancement or hydrocephalus, complete neuroaxis MR imaging should be obtained. Cytological examination of the CSF can be used to confirm the diagnosis. Additional treatment modalities available to these patients are outlined later in this discussion.
Multifocal and multicentric GBM do not exhibit any histopathologic characteristics that differentiate them from typical, solitary supratentorial GBM [10
]. Pathognomonic features of GBM include pseudopalisading necrosis and neovascularization [21
]. The individual tumors in cases of multicentric GBM usually have the same pathologic appearance [10
Although there is still no unified theory regarding the pathogenesis of multifocal and multicentric GBM, several hypotheses have been developed. According to earlier theories, multicentricity arises from two events [8
]. The first stage is neoplastic transformation, in which a wide field becomes more susceptible to neoplastic growth. The second stage is tumor proliferation at two or more activated sites that can occur simultaneously in response to various stimuli including biochemical, hormonal, and viral triggers. More contemporary theories have looked at molecular associations. For example, there is a reported association between p53
mutations and multifocal GBM that correlates the pattern of p53
mutation to tumor migration and augmented growth [23
]. In a study of the growth factor receptor c-Met in GBM, one group found that 42.9% of tumors that overexpressed c-Met displayed invasive and multifocal features on initial MR imaging, whereas only 17.1% of tumors with little or no c-Met expression had similar characteristics (P
= 0.036) [25
]. This molecular and genetic characterization of multifocal GBM has thereby implicated particular oncogenes and growth factors in the pathogenesis of multifocal and multicentric GBM.
In addition to the molecular pathways involved in multifocality and multicentricity, studies have correlated the tumor pattern at diagnosis and recurrence with the spatial relationship to the subventricular zone (SVZ) and cortex as seen on MR imaging [26
]. More specifically, patients with a contrast-enhancing lesion contacting the SVZ and infiltrating the cortex were most likely to have multifocal disease at the time of diagnosis and distant tumor recurrence. On the other hand, patients with a contrast-enhancing lesion neither contacting the SVZ nor infiltrating the cortex always had solitary lesions and contiguous tumor recurrences. Neural stem cells within the SVZ may give rise to multiple and multicentric GBM. Neural stem cells have been found to express matrix metalloproteinases, which are proteolytic enzymes implicated in tumor spread [26
]. Furthermore, the SVZ is thought to be a highly permissive environment for tumor growth and cellular migration.
Currently, there are no clear guidelines regarding the optimal management of multifocal and multicentric GBM [15
]. While the extent of resection is established as an independent determinant of survival in patients with solitary GBM, the role of surgery for multifocal and multicentric GBM remains controversial [6
]. Aggressive resection of one tumor focus, biopsy alone followed by chemotherapy and radiation treatment, and multiple craniotomies during a single operation have all been described with no clear indication of which modality is superior [15
]. The standard radiation treatment for GBM includes conformal radiotherapy that encompasses the tumor volume and margin along with concurrent and adjuvant temozolomide [4
]. Regarding radiotherapy for multifocal and multicentric GBM, a study found no significant difference in the median time to progression or median survival time between conformal radiotherapy and whole brain radiation treatment [30
]. Additionally, the role of radiotherapy to control infratentorial GBM is not yet defined [32
]. Some studies support the use of craniospinal radiotherapy with posterior fossa boost for malignant cerebellar gliomas, especially in children [33
]. However, other studies have found no benefit with craniospinal radiotherapy in GBM in adults and support whole brain radiation treatment with or without posterior fossa boost [32
]. Most authors agree that craniospinal irradiation is reasonable if CSF dissemination occurs [34
]. In patients with leptomeningeal gliomatosis, other treatments could also include intrathecal chemotherapy and CSF shunting for associated hydrocephalus.