CHAPTER 122 Malignant Gliomas
Anaplastic Astrocytoma, Glioblastoma Multiforme, Gliosarcoma
Malignant astrocytomas, which include anaplastic astrocytoma (AA, World Health Organization [WHO] grade III) (Fig. 122-1, Table 122-1), glioblastoma multiforme (GBM, WHO grade IV) (Fig. 122-2, Tables 122-2 and 122-3), and gliosarcoma, are the most common malignant primary central nervous system (CNS) tumors in adults.1 Even with optimal treatment, median survival is only less than 2 years for patients with glioblastoma and 2 to 5 years for patients with anaplastic glioma.1–3 Malignant astrocytoma is characterized by its invasive and infiltrative nature, which makes curative resection unlikely.4 In the 1930s, Walter Dandy reported recurrence of contralateral gliomas even after hemispherectomy of the tumor-bearing hemisphere, thus illustrating how infiltrative these tumors are.5 The survival of these patients was still less than 2 years despite such aggressive resection.5 Advances have been made to steadily increase the survival of patients with these tumors. Four randomized, prospective, controlled multi-institutional trials have led to two new treatments that have received Food and Drug Administration approval for malignant gliomas.6–9 Brem and colleagues found that the use of carmustine-loaded biodegradable polymers improved survival in patients with recurrent malignant gliomas from 23 weeks to 31 weeks after revision resection (Fig. 122-3).6 Valtonen and associates found that the median time from surgery to death in patients with high-grade glioma was 58.1 weeks for those who received carmustine combined with a biodegradable polymer versus 39.9 weeks for the placebo group.8 Moreover, GBM patients treated with carmustine combined with a biodegradable polymer survived 53.3 weeks versus 39.9 weeks for the placebo group.8 In a multicenter long-term study by Westphal and coworkers, patients treated with Gliadel (carmustine with a biodegradable polymer) had a median survival of 13.8 months versus 11.6 months in placebo-treated patients.7 Stupp and coauthors reported a median survival of 14.6 months for patients with GBM after surgical resection, radiotherapy, and temozolomide chemotherapy.9 Advances in surgical adjuncts include intraoperative image-guided stereotaxis, functional magnetic resonance imaging (MRI),10,11 cortical mapping,12–14 and intraoperative MRI.15 Although these additions are aimed at assisting in increasing the extent of tumor resection, there is conflicting evidence whether the extent of resection is associated with improved survival of patients with high-grade glioma.16–21 This review focuses on AA, GBM, and gliosarcoma and discusses the epidemiology, molecular genetics, diagnosis, and surgical treatment, including the most recent data on the association between the extent of resection and survival of patients with these malignant lesions.
TABLE 122-1 Variables Associated with Overall Survival after Resection of World Health Organization Grade III Astrocytoma in Univariate and Multivariate Proportional Hazards Regression Analysis (Cox Model)
TABLE 122-2 Variables Associated with Overall Survival after Primary Resection of Glioblastoma Multiforme in Univariate and Multivariate Proportional Hazards Regression Analysis (Cox Model)
TABLE 122-3 Variables Associated with Overall Survival after Revision Resection of Glioblastoma Multiforme in Univariate and Multivariate Proportional Hazards Regression Analysis (Cox Model)
Epidemiology
Anaplastic Astrocytoma and Glioblastoma Multiforme
Malignant astrocytomas are the most common primary brain tumor in adults. Primary malignant CNS tumors account for about 2% of all cancers but cause a disproportionate rate of cancer-related morbidity and mortality.2,22 An estimated 43,800 new cases of benign and malignant brain tumors are diagnosed annually in the United States.22 Of these patients, approximately 12,760 will die.22 The incidence of brain tumors is 14.8 per 100,000 person-years, with approximately half being histologically malignant.22 Malignant CNS tumors are the leading cause of death from solid tumors in children and the third leading cause of cancer-related death in adolescents and adults aged 15 to 34 years.22 The average age at which AAs develop is approximately 40 years,23 as opposed to GBM, which has a mean age of 53 years with a peak incidence between the ages of 65 and 74.23,24 GBM is more common in men, with a male-to-female ratio of 1.5:1.25 There has been some controversy over a possible increase of approximately 1% to 2% per year in the incidence of brain tumors during the 1980s and 1990s,26,27 particularly in the elderly,28–30 as well as in children.31 Some studies indeed show a true increase in incidence rates independent of a greater ability to detect and diagnose brain tumors because of diagnostic improvements.2 This increase in the incidence of brain tumors may be due to the introduction of high-resolution neuroimaging, which has tremendously improved the clinical diagnosis of neurological diseases.32–34 Population-based incidence data from the Netherlands Cancer Registry have demonstrated a stable incidence of both childhood and adult gliomas.35 In adult gliomas, a significantly increasing incidence of high-grade astrocytoma was balanced by simultaneous decreases in low-grade astrocytoma, astrocytoma with unknown malignancy grade, and glioma of uncertain histology.35 Similar findings have been reported by Hoffman and coauthors, who analyzed data from six collaborating cancer registries of the Cancer Brain Tumor Registry of the United States (CBTRUS) from 1985 to 1999.36 Thus, these time trends may be explained at least in part by improvements in detection and diagnostic precision.
Gliosarcoma
Gliosarcomas represent between 2% and 8% of cases of GBM (WHO grade IV).37–41 The clinical findings and prognosis are similar in gliosarcoma and GBM.39 Meis and coworkers reported that there were no significant differences between gliosarcoma and GBM with regard to age, sex, pretreatment Karnofsky Performance Status (KPS) score, median survival, tumor location, and size.39 Most cases of gliosarcoma occur between the ages of 40 and 60, with a mean age of 53 years.39,40 However, gliosarcoma may also occur in children, and in rare cases infantile gliosarcoma has even been reported.42 Gliosarcoma occurs more frequently in males than females at a male-to-female ratio of 1.8:1.39,40
Clinical Manifestations
Anaplastic Astrocytoma and Glioblastoma Multiforme
AA and GBM often occur in the cerebral hemispheres.23 They can arise from low-grade astrocytoma (WHO grade II) but can also be diagnosed de novo at first biopsy without signs of a malignant precursor.23,43 AA has an innate tendency to progress to GBM. Like GBM, AA tends to recur locally, often at the margins of the tumor resection and even when gross total resection (GTR) has been performed.14 The symptoms and signs are relatively uniform but nonspecific in patients with GBM. Commonly, patients will have raised intracranial pressure, which may lead to headache, nausea and vomiting, blurred or double vision, and drowsiness. These signs and symptoms may be associated with extraocular palsies, objective papilledema, pupil abnormalities, or decreased level of consciousness. They are typically more prominent in the morning and improve over the course of the day. Relentless progressive headaches are a hallmark of the symptomatology of these tumors. Up to a third of patients with GBM have seizures. Neurological deficits are common and vary according to the location and extent of tumor infiltration. These deficits may be focal or global (altered cognition and change in personality). Although common in AA and GBM patients, neurological deficits from these lesions are often subtle and may go unrecognized until after the brain tumor is detected.
Gliosarcoma
The most common primary localization of gliosarcoma is in the temporal lobe, but these lesions also occur in the parietal, frontal, and occipital lobes (in decreasing order of frequency).30,39,41,44–47 Multifocal display of cerebral and cerebellar gliosarcomas has also been reported.48,49 GBM and gliosarcoma can spread into the cerebrospinal fluid pathways and invade the ventricles, cranial nerves, leptomeninges, and spinal cord.50,51 Gliosarcoma has a tendency toward peripheral brain localization and dural attachment.30,41,52–57 Jack and colleagues found that in contrast to AA and GBM, gliosarcoma has a marked tendency toward dural invasion and had a mixed dural and pial vascular supply in nearly half the cases.55 Despite similar features with glioblastoma, gliosarcoma has been found to metastasize much more frequently than glioblastoma, with extracranial metastases being reported in 15% to 30% of patients with gliosarcoma (Table 122-4).56–66 Metastases to visceral organs,56–60,62,63,65–70 as well as the spinal cord,51,61,65 have been reported. Metastatic tumor deposits usually contain both sarcomatous and glial cells, although there have been isolated reports of tumor deposits containing sarcomatous cells only.41,57,67
TABLE 122-4 Clinical Data on Representative Metastatic Gliosarcomas As Reported in the Recent Literature
Gliosarcomas behave similarly to glioblastomas.38,39,41,44 Symptoms are largely determined by the location of the primary tumor and the presence of raised intracranial pressure.71 The most common symptoms of gliosarcoma are headache and hemiparesis, although nausea, seizures, and personality change may also occur. The most common signs of gliosarcoma are focal weakness, visual field defects, papilledema, and dysphasia.40,41,50
Histopathology
Anaplastic Astrocytoma and Glioblastoma Multiforme
Part of the reason that malignant gliomas are so lethal is that they grow by invasion, thus limiting the efficacy of surgery and other therapies (Figs. 122-4 and 122-5).72–74 Malignant glioma cells have been demonstrated to have great motility in both in vitro and in vivo rodent models.75–78 Increasing grade of glioma and exposure to growth factors, such as epidermal growth factor, increase the motility of the cells.79–82 Autopsy studies have shown that high-grade gliomas usually extend beyond a single carotid or vertebral artery distribution, often spread through the cerebrospinal fluid pathways, and may extend past the 2-cm margins demonstrated by computed tomography (CT) or MRI.73,83,84 Even after seemingly curative resection of these tumors, there are frequently microsatellites of tumor cells scattered throughout normal brain tissue that have the potential to continue proliferating and cause tumor recurrence in other areas of the brain.85 Infiltration of tumor into eloquent areas of the brain may limit the extent of tumor resection.86–88 As far back as 1928, Walter Dandy reported recurrence of contralateral gliomas even after hemispherectomy.5 Stereotactic biopsy samples obtained from brain regions distant from enhancing tumor, as delineated by MRI, show that areas with high signal intensity on T2-weighted images contain tumor cells.84 Biopsy of regions beyond any MRI signal abnormalities produces specimens that are histologically normal but nevertheless have been demonstrated to contain tumor cells with in vitro culture techniques.89 Thus, imaging techniques and histology have limited resolution in estimating the true extent of tumor cell invasion and thus inevitably underestimate the true extent of these tumors.
The current classification systems for malignant gliomas rely on the histologic characteristics of these lesions. The tumor size, nodal status, and metastasis (TNM) system that is used for many systemic cancers is not applicable to the grading of gliomas because these lesions rarely metastasize beyond the CNS. The utility of any particular glioma classification system has traditionally been validated by assessing how well it can predict length of survival. Cell lineage and thus the specific type of high-grade glioma can be determined with antibodies directed against specific cell markers. The WHO classification of brain tumors was first published in 197990 and then modified in 1993,91 2000,92 and 2007.93 Although imperfect, controversial, and without molecular basis, the current WHO system is the most widely used classification system for gliomas.91 Even though a wealth of genomic data have been added recently,57 morphology is still the “gold standard” of the WHO classification. The classification system consists of a four-tiered schema that includes pilocytic astrocytoma (WHO grade I), low-grade astrocytoma (WHO grade II), AA (WHO grade III), and GBM (WHO grade IV). WHO grade II tumors may have nuclear atypia. WHO grade III tumors display mitotic activity and nuclear atypia. WHO grade IV tumors show nuclear atypia, mitoses, and endothelial proliferation or necrosis.
Uncommon glioblastoma variants include gliosarcoma, which contains a prominent sarcomatous element; giant cell glioblastoma, which has multinucleated giant cells; small cell glioblastoma, which is associated with amplification of epidermal growth factor receptor (EGFR); and glioblastoma with oligodendroglial features, which may be associated with a better prognosis than standard glioblastomas.40,94
In addition to the WHO classification system, the MIB-1/Ki-67 labeling index is often included in the pathology reports of these tumors. The labeling index increases proportionally with tumor grade. AA (WHO grade III) typically has a labeling index in the range of 5% to 10%, although values vary considerably, even within different regions of the tumor itself.44,95–97 GBM (WHO grade IV) can also show extensive heterogeneity, with a mean labeling index generally between 10% and 20%.44,96,98,99
Molecular Biology
There has been tremendous progress in our understanding of the molecular pathogenesis and origin of malignant gliomas, especially with regard to cancer stem cells.100,101 Malignant transformation of gliomas results from the sequential accumulation of genetic mutations and deregulation of growth factor signaling pathways or failure of the cell cycle control mechanisms, or both.100–102 Significant advances have been made in elucidating the biology of gliomas. In 2008, Parsons and colleagues sequenced more than 20,000 protein-coding genes in 22 human GBM samples and found a new mutated gene, isocitrate dehydrogenase 1 (IDH1), shared by many patients with secondary GBM.57 This study illustrates the powerful ability that new and emerging research technologies have in enhancing our understanding of the biology of these tumors and discovery of new targets for future therapies.
Glioblastomas have traditionally been separated into two main subtypes, primary and secondary glioblastoma. These subtypes are morphologically indistinguishable and respond similarly to conventional therapy. However, they differ biologically and genetically and thus may respond differently to targeted molecular therapies.100,102 Primary glioblastomas are typically seen in patients older than 50 years and are characterized by EGFR amplification and mutations, loss of heterozygosity of chromosome 10q, deletion of the phosphatase and tensin homologue on chromosome 10 (PTEN), and deletion of chromosome p16. Secondary glioblastomas have transcriptional patterns and aberrations in DNA copy number that significantly differ from those of primary glioblastomas.100,102 These tumors occur in younger patients as low-grade astrocytoma or AA and then transform over a period of several years into glioblastoma. Secondary glioblastomas are much less common than primary glioblastomas and are characterized by mutations in the TP53 tumor suppressor gene,66 overexpression of platelet-derived growth factor receptor (PDGFR), abnormalities in the p16 and retinoblastoma (Rb) pathways, and loss of heterozygosity of chromosome 10q.100,103 It has recently been discovered that a specific mutation of IDH1 was present in 70% of WHO grades II and III astrocytomas and oligodendrogliomas, as well as in glioblastomas that developed from these lower grade lesions.57 Moreover, mutations of the oxidized nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant glioma, especially in secondary glioblastomas.57
The most common mutations involve tumor suppressor genes involved in cell cycle control, such as TP53 and PTEN. TP53 mutations occur more commonly in secondary GBM, whereas PTEN mutations occur more commonly in primary GBM.102,104,105 PTEN, a tumor suppressor gene that negatively regulates the phosphatidylinositol-3′-kinase (PI3K) pathway, is inactivated in 40% to 50% of patients with glioblastoma.100,106 Although PTEN mutations are frequently observed in GBM, these mutations are rare in lower grade astrocytic tumors.40 Compromised PTEN function may contribute to gliomagenesis through disrupted regulation of proliferation, stem cell self-renewal, angiogenesis, migration, invasion, and regulation of other tumor suppressor pathways such as TP53.107 TP53 plays a role in several cellular processes, including the cell cycle, response of cells to DNA damage, cell death, cell differentiation, and neovascularization.108 TP53 mutations are the first detectable genetic mutations in two thirds of precursor low-grade diffuse astrocytomas, and its frequency is similar to that of AAs and secondary glioblastomas derived thereof.66,109,110 TP53 mutations also occur in primary glioblastomas, but at a lower frequency (<30% of cases).110
Aberrations in the growth factor signaling pathways involving EGFR and PDGFR are also very prominent and play an important role in primary and secondary GBM.100 Amplification or mutation of EGFR occurs almost exclusively in primary GBM and is seen in approximately 40% to 50% of patients with these tumors. About half of tumors with EGFR amplification express a constitutively autophosphorylated variant of EGFR known as EGFRvIII that lacks the extracellular ligand-binding domain.94,100 This EGFRvIII variant has become an important therapeutic target for kinase inhibitors, immunotoxins, and peptide vaccines.100,111 Activating mutations in the extracellular domain of EGFR have also been identified.112 PDGFR signaling is very important in glial development.113 A PDGFR autocrine loop is frequently present in gliomas because the tumor cells express high levels of both ligand and receptor in this pathway, thereby ultimately stimulating proliferation of the tumor.100 Growth factor receptor signaling (i.e., PDGFR, EGFR) through intermediate signal transduction generators results in the activation of transcriptional programs for survival, proliferation, invasion, and angiogenesis. Common signal transduction pathways activated by these growth factors are the PI3K-Akt-mTOR (mammalian target of rapamycin) pathways, which are involved in cellular proliferation and inhibition of apoptosis, and the Ras-MAPK (mitogen-activated protein kinase) pathway, which is involved in cell cycle progression and proliferation.100 Many of these pathways lead to the upregulation of vascular endothelial growth factor (VEGF), which promotes angiogenesis.114,115
Role of Stem Cells in Pathogenesis and Resistance to Therapy
Although there has been great progress in characterizing the genetic mutations and signaling pathways involved in the development of malignant gliomas, the cellular origins of these tumors are unknown. The adult nervous system has been discovered to harbor neural stem cells that are capable of self-renewal, proliferation, and differentiation into distinctive mature cell types.116,117 There is now increasing evidence that these neural stem cells, or related progenitor cells, can be transformed into brain tumor stem cells and give rise to malignant gliomas by escaping the mechanisms that control proliferation, programmed differentiation, and apoptosis.118–122 These stem cells are identified by several immunocytochemical markers, such as CD133 (prominin 1) and nestin.106,118,121,123,124 Although stem cells are only a small subpopulation of cells within malignant gliomas, they appear to be critical for generating these tumors and maintaining their bulk.122,125 Glioma stem cells have been shown to produce VEGF and promote angiogenesis in the tumor microenvironment.126 Moreover, tumor stem cells have been found to require a vascular niche for optimal function.127 Thus, antiangiogenic therapy has potential for inhibiting the functioning of glioma stem cells.
Gliosarcomas
Gliosarcoma is a rare glioblastoma variant characterized by a biphasic tissue pattern with glial and mesenchymal components.37,40,58,128,129 The glial portion of gliosarcomas consists most commonly of astrocytes with nuclear atypia and mitotic figures.41 The sarcomatous region consists of neoplastic mesenchymal cells with associated reticulin formation.40 These cells are spindle shaped and demonstrate nuclear atypia, increased mitotic activity, and necrosis. Glial fibrillary acidic protein (GFAP) immunostaining is an important tool for distinguishing between gliosarcoma and other tumors such as glioblastoma or pure sarcoma.39 GFAP is present in glial regions but found in very low quantities in sarcomatous regions.47 Strong staining for vimentin, which is a marker for mesenchymal cells, occurs mostly in sarcomatous areas with scarce staining in glial regions.47 Likewise, there is no reticulin staining in glial regions, except around blood vessels, but sarcomatous regions are rich in reticulin.47
Gliosarcoma usually appears as a tough, well-circumscribed lobular mass often attached to the dura and at surgery may resemble a meningioma (Fig. 122-6).53,54 These tumors frequently contain areas of necrosis that are predominantly located in the poorly defined, soft astrocytic component.54,55 The sarcomatous component of these tumors is firm and well circumscribed, which often facilitates separation of it from adjacent brain tissue.54,55
Neuroimaging Studies
Anaplastic Astrocytoma and Glioblastoma Multiforme
Although skull radiography, angiography, and CT were the major diagnostic modalities of brain imaging in the past, MRI is now the preferred study for brain tumors. CT is used in the acute environment as the first line of imaging to exclude hemorrhage or large areas of infarction in the brain. CT is particularly adept at delineating acute hemorrhage, as well as intratumoral calcification. However, once a mass lesion is suspected on non–contrast-enhanced CT, MRI is used to better characterize the mass because of its multiplanar capability and superior soft tissue contrast. Gadolinium contrast agent can enhance soft tissue contrast, further elucidate the boundaries of the tumor, and provide information about the integrity of the blood-brain barrier by detecting areas of blood-brain barrier breakdown. Standard T1- and T2-weighted MRI studies are able to detect brain tumors with high sensitivity with regard to size and localization. They are also able to detect mass effect, edema, hemorrhage, necrosis, and signs of increased intracranial pressure. High-grade glioma normally appears as an irregular hypodense lesion on T1-weighted MRI with various degrees of contrast enhancement and edema. The presence of ring-like enhancement surrounding irregularly shaped areas of presumed necrosis suggests glioblastoma (see Fig. 122-5A and B).130 However, AAs can appear as nonenhancing tumors, and even glioblastomas may initially be manifested as a nonenhancing lesions, especially in older patients (see Fig. 122-4A).131 Moreover, low-grade gliomas may occasionally demonstrate contrast enhancement.131 Functional MRI can be used to define the locations of functionally eloquent cortex, such as the motor cortex, Broca’s area, Wernicke’s area, and the visual cortex. It is important to note that in up to 40% of cases, MRI studies performed in the first month after radiotherapy may show increased enhancement.132 In 50% of these cases that show enhancement in the first month after radiotherapy, the increased enhancement reflects a transient increase in vessel permeability that is a result of radiotherapy, a phenomenon that improves with time and is designated “pseudoprogression.”132
