Chapter 34 Low-Grade and High-Grade Gliomas
• Low-grade gliomas (LGGs) account for 15% of primary adult tumors diagnosed, and in adults they mainly occur in supratentorial areas, particularly in the insular and supplementary motor areas.
• LGGs comprise astrocytomas, oligodendrogliomas, and oligoastrocytomas.
• Factors such as age less than 40 years, Karnofsky performance scale (KPS) score of 70 or greater, absence of contrast enhancement, and oligodendrogliomas are associated with a better prognosis for LGGs.
• The extent of surgical resection probably correlates with a better survival for LGGs, but resection must be tempered by their location close to the eloquent area. Motor-sensory mapping, language mapping, and diffusion tensor imaging should be used to assess tumors adjacent to critical regions.
• Postoperative radiotherapy is often used for LGGs and provides improved progression-free survival but does not extend overall survival.
• A better response to chemotherapy is seen in patients with oligodendrogliomas, which exhibit combined 1p/19q loss of heterozygosity.
• High-grade gliomas (malignant gliomas and glioblastoma multiforme [GBM]) may arise in progression from low-grade astrocytic tumors (secondary GBMs) or as de novo lesions (primary GBMs). There are distinct genetic differences between these two groups of tumors.
• Factors such as a younger age group, lower tumor histological grade, and higher KPS score are associated with a better prognosis for high-grade gliomas.
• The extent of resection (absence of class 1 evidence) has a probable influence on survival. Both radiotherapy and temozolomide chemotherapy significantly increase survival time of these patients.
• Advances in molecular markers may open avenues for new therapies.
Low-Grade Gliomas
A Perspective on Management
There are currently a number of considerations involved in the management of patients with low-grade gliomas (LGGs), which, for the purposes of this discussion, will be defined as World Health Organization (WHO) grade II gliomas. Advances in tumor biology, neuroimaging, and treatment paradigms have enabled the neurosurgeon to approach these patients with a better understanding of the disease entity and its natural history. However, many controversial issues remain unanswered. Diagnostic strategies previously considered reliable for LGG patients, including structural magnetic resonance imaging (MRI) and stereotactic biopsy, have more recently been shown to vary substantially with regard to specificity, sensitivity, and sampling error. Surgical management paradigms are also shifting, as mounting evidence now highlights the predictive value of volumetric tumor burden for patient survival, the role of greater extent of resection in reducing malignant transformation rates, and the influence of tumor eloquence in determining resectability. Additionally, LGG-associated seizures are increasingly considered as a key determinant of quality of life, with electrocorticography being used as an effective surgical adjunct in this regard when seizures are medically refractory. Adjuvant therapies are also under renewed scrutiny. Although the utility of radiation therapy is clear, the timing and type of chemotherapy remain somewhat uncertain, as does the role of new molecular therapeutics. Taken together, these new innovations and controversies define the modern era of LGG management. Here we review the current literature in an effort to highlight high-impact developments that are changing our view of LGGs, as well as the pivotal studies that should guide neurosurgeons as they consider these many issues.
Epidemiology
LGGs are not uncommon, representing 15% of all primary adult brain tumors diagnosed each year. They are most frequent among white men and typically affect patients at a younger age than high-grade gliomas (fourth vs. sixth decade of life). Even though LGGs are diffusely distributed along a variety of supratentorial regions, they have a particular predilection for the insula and supplementary motor area. In contrast, LGGs rarely involve the cerebellum, brainstem, or spinal cord, as is commonly found in children. Most patients initially present with relatively good neurological function, and seizures are the most common symptom at presentation (80%). The only definite risk factor for LGG is previous exposure to ionizing radiation.1 Hereditary factors do not play a substantial role in the development of LGGs, although these tumors are more common in patients with neurofibromatosis type 1 and Li-Fraumeni syndrome. From 15% to 20% of individuals with neurofibromatosis type 1 develop LGGs affecting the optic nerves, optic chiasm, and hypothalamus (optic pathway gliomas). Most of these gliomas are classified as WHO grade I tumors, although grade II LGGs can also occur in these locations.2
The etiology of adult LGGs is largely unknown and is thought to be multifactorial; various genetic, infectious, and immunological factors have been implicated. Glioma epidemiology studies have revealed few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions, but larger consortium efforts have outlined several potential risk factors for gliomagenesis and outcome.1 Data from the Surveillance, Epidemiology, and End Results (SEER) Program indicated that African Americans had similar or poorer survival than whites,3 but those results were adjusted incompletely for important prognostic factors (e.g., age at diagnosis, treatment patterns, and tumor histological types). After adjustment, African Americans had a 40% higher risk of death from low-grade tumors compared with non-Hispanic whites.4 Likewise, risks from specific neurocarcinogens have yet to be identified; however, the continued occurrence of brain tumor clusters leaves open the question of the effect and extent of their exposures. Observations of an association between drinking water and brain tumors suggest that ingestion of an environmental contaminant has an impact,5–7 perhaps from chlorinated sources like chloroethane, a by-product of sewage treatment, or nitrate/nitrite contamination of drinking water supplies.
Recent epidemiological studies have also reported that adults with low- as well as high-grade gliomas are 1.5- to 4-fold less likely than control subjects to have allergies, which ranks the lack of allergies among the most consistent risk factors for glioma reported to date. In addition, an inverse relationship exists between immunoglobulin E (IgE), a biomarker for atopic allergy, and glioma risk. Interestingly, the strongest IgE-glioma association has been observed among the least prevalent allergen—food IgE. Low- and high-grade glioma patients with elevated levels of IgE are associated with an approximately 8 months’ longer survival than individuals with lower or undetectable levels, demonstrating the potential clinical significance of such correlates.8
Classification
Oligodendrogliomas occur in the white matter and cortex of the cerebral hemispheres and show a monotonous pattern on low power with occasional nodules of higher cellularity. Unlike WHO grade II astrocytomas, the presence of low mitotic activity, vascular proliferation, and necrosis, including pseudopallisading necrosis, are insufficient by themselves to elevate the grade of WHO grade II oligodendrogliomas. Their nuclei are round and regular, and clear perinuclear halos are present in most paraffin-embedded specimens. This typical “fried egg” appearance is a formalin fixation artifact and is therefore not seen in frozen sections, smears, or rapidly fixed specimens. Oligoastrocytomas are a recognized category of LGGs, but are ill-defined, prone to subjectivity, and based on an unproven concept of dual differentiation of astrocytoma and oligodendroglioma as neoplastic processes.9 Histologically, they are defined by a mixture of cells, some with oligodendroglioma features, and others resembling diffuse astrocytomas. Currently, there are no standardized immunohistochemistry or molecular panels to distinguish oligoastrocytomas from other LGGs.
Clinical Presentation
Patients with LGGs present with signs and symptoms of disease related to direct parenchyma infiltration; local tumor effects due to edema, hemorrhage, or tumor mass; or intracranial hypertension mediated by mass effects or ventricular obstruction. Although the onset of symptoms can be subtle and insidious, when patients become symptomatic, seizure is the most common presenting sign, occurring in up to 80% of cases;10 this is probably due to the superficial localization and low growth rate of the tumor in many cases. Other, less common clinical presentations include headache, lethargy, and personality changes, although these symptoms, caused by raised intracranial pressure, are rare.
Prognostic Factors
Although substantial heterogeneity exists when profiling LGG patient outcome, several clinical factors are known to be predictive. Chief among those is age over 40 years, a predictive factor identified in multivariate analyses from two large, prospective trials.11,12 Age at the time of LGG diagnosis is not only inversely correlated with time to progression, but tumor proliferative index may be higher among those older than 40 years as well.13 Although the biology behind this association is unclear, one possibility is that age-related impairment of DNA repair mechanisms and the resulting acquisition of mutations may promote rapid progression after transformation occurs. Clinical presentation is another strong prognostic factor, as neurologically intact patients presenting with isolated seizures typically have a better performance status and overall prognosis. LGG patients who present with seizures also tend to be younger and have smaller tumors than those without seizure.14
An LGG preoperative prognostic scoring system developed at the University of California at San Francisco (UCSF) assigns a prognostic score based upon the sum of points assigned to the presence of each of the four following factors (1 point per factor): (1) location of tumor in presumed eloquent cortex, (2) Karnofsky performance scale (KPS) score 80 or less, (3) age more than 50 years, and (4) maximum diameter more than 4 cm. Cox proportional hazard modeling was used to confirm that the individual factors were associated with shorter overall survival (OS) and progression-free survival (PFS); and Kaplan-Meier curves estimated OS and PFS for the score groups.15 Low-risk tumors are considered grades 0 or 1, and high-risk tumors are grade 4. This scoring system accurately predicted OS and PFS in a multi-institutional population of LGG patients.16
The median survival for oligodendrogliomas is approximately 15 years, a better prognosis than for astrocytomas, which have a median survival of 10 years.17 Gemistocytic astrocytomas, a subtype of grade II astrocytomas, are more aggressive than predicted by grade.18 Large tumors, nonlobar gliomas, and tumors that cross the midline are associated with a short survival and a high rate of malignant transformation.11 Preoperative tumor burden is also associated with less extensive resection, which in turn portends poorer outcome.19 Proliferative index has also been inversely related with LGG outcome, as has contrast enhancement.20
Recent work in glioma outcomes research also suggests that more unconventional factors may play a role in LGG patient outcome. For example, among patients with nonanaplastic oligodendroglial tumors, younger age and surgical resection versus biopsy were significantly associated with better survival, as expected. Interestingly, however, those patients who were college graduates also showed significantly better survival in age-adjusted comparisons.21 Further consideration of impact of marital status, education, and other social factors in glioma survival may be warranted, as these factors also appear to be significant in predicting high-grade glioma outcome.
Efforts to synthesize LGG risk factors into distinct prognostic classes have led to four categories of patients: (1) younger patients (18-40 years of age) with a good performance status (KPS score ≥ 70) have a median survival of more than 10 years; (2) younger patients with a poor performance status (KPS score < 70) and older patients (>40 years of age) with a good performance status and no contrast enhancement had a median survival of more than 7 years; (3) older patients with a good performance status and with contrast enhancement had a median survival of less than 4 years; and (4) older patients with a poor performance status had a median survival of only 12 months.22 It remains unclear, however, how tumor extent of resection impacts the predictive value of each category following resection because it was not evaluated in that study.
Similarly, the EORTC (European Organization for Research and Treatment of Cancer) developed a prognostic scoring system based on two large, randomized, multicenter trials with more than 600 patients.11,12 In their multivariate analysis, age older than 40 years, astrocytic tumor type, tumor size greater than 6 cm, tumor crossing the midline, and neurological deficit at diagnosis were retained in the model. A favorable prognostic score was defined as no more than two of these adverse factors and was associated with a median survival of 7.7 years. The presence of three to five prognostic factors was associated with a median survival of 3.2 years (95% confidence interval [CI] = 3.0, 4.0).
Diagnostic Imaging
The 1.5-tesla MRI remains the imaging gold standard for noninvasive identification and diagnosis of LGGs, although the emergence of 3-tesla magnets has improved image resolution considerably.23 LGGs are characteristically homogeneously isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images. The epicenters of low-grade astrocytomas are typically within the white matter, whereas oligodendrogliomas can be more superficial and will occasionally expand the adjacent gyrus. Contrast enhancement is uncommon, but more often is seen in oligodendrogliomas (25-50%). Calcifications are apparent in 20% of lesions and are characterized by foci of high T1 and low T2 signals. Vasogenic edema and mass effect are uncommon because of the slow-growing nature of these tumors. Rarely, large LGGs will involve three or more cerebral lobes (gliomatosis cerebri). Diffusion tensor imaging has proved to be an essential adjunct to structural imaging for both preoperative planning and intraoperative neuronavigation. Specification of functional tract deflection around a lesion can not only alter the operative approach, but can dictate the limits of resection. Modalities such as functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) can aid in preoperative planning by identifying these functional pathways, although these techniques remain too imprecise for complex functions such as language mapping, as their sensitivity (positron emission tomography [PET], 75%; fMRI, 81%) and specificity (PET, 81%; fMRI, 53%) remain suboptimal.24–27 For the identification of peritumoral language pathways, direct intraoperative stimulation mapping remains the gold standard. Intraoperative MRI is another operating room technology that may impact LGG outcome. Through real-time guidance, it allows for localization of tumors and their margins, and facilitates continuous assessment of surgical progress. Studies of LGG patients who underwent resection in an intraoperative MRI suite report encouraging results in terms of achieving greater extent of resection.28,29
However, using standard structural imaging paradigms, the decision to presume low-grade histological type on the basis of a nonenhancing lesion is a common mistake. For patients with supratentorial mass lesions that exhibit the typical imaging features of LGG, structural MRI has a false positive rate as high as 50% when attempting to predict the histological diagnosis of astrocytoma.30 This risk of anaplasia in MRI nonenhancing lesions increases significantly with patient age.31 Thus, observation of LGGs is not a prudent option, and early tissue diagnosis is essential. These misleading imaging features are likely due to the intrinsic heterogeneity of LGGs, a characteristic evident on physiological MRI such as magnetic resonance spectroscopy (MRS), which can demonstrate pockets of high-grade populations nested within the tumor stroma.32 Thus, stereotactic biopsies should be planned using MRS guidance to target putative high-grade components in nonenhancing tumors.
Next-generation structural MRI technologies have recently focused on preoperatively defining LGGs. Microscopic molecular movement of water in tumor tissue reflects tissue properties that include varying levels of structural alterations, tumor cellularity, and vasogenic edema. Diffusion-weighted MRI (DWI) uses strong gradients to probe the structure of biological tissues at a microscopic level by measuring the brownian motion of water molecules. Acquiring data with gradients in three directions allows the calculation of the apparent diffusion coefficient (ADC), while acquiring data with gradients in six or more directions allows the calculation of the ADC and the fractional anisotropy (FA). Recent work using these emerging imaging paradigms attempted radiographic prediction of specific LGG subtypes. Interestingly, initial attempts demonstrated a significant difference in the ADC and FA values between newly diagnosed patients with grade II oligodendrogliomas and astrocytomas, and patients with the heterogeneous grade II oligoastrocytomas had values that fell in between.33 However, although ADC has been suggested to correlate to cell density in a mixed population of glioma patients, it remains unclear whether this parameter is what drives its correlation with specific LGG subtypes.
The emergence of physiological imaging techniques has indeed added a new dimension to LGG diagnosis and targeting.34 Proton MRS imaging (1H-MRSI) is another emerging modality that identifies the distribution of cellular metabolite levels. Five classes of molecules are generally observed in brain spectra: N-acetylaspartate (NAA); free choline and choline-containing compounds, including phosphocholine and glycerophosphocholine (Cho); creatine and phosphocreatine (Cr); lactate (Lac); and lipid (Lip). Using MRS, typical spectra of LGG include a dominant choline peak (reflecting increased membrane synthesis) with low-intensity N-acetylaspartate (reflecting decreased neuronal elements) and no quantifiable lipid or lactate (suggesting an absence of necrosis or hypoxia, respectively; both features of high-grade gliomas). The choline peak may be associated with cellular density and cellular proliferation, thereby improving selection of targets for biopsy. Normalized creatine/phosphocreatine levels (tCr) of LGGs are a significant prognostic factor for progression-free survival, as well as malignant progression-free survival.35 Newly introduced three-dimensional (3D) techniques allow whole anatomical regions to be quantified metabolically, correlating well with the region of T2 hyperintensity, as well as with tumor extension along white matter tracts.36 Three-dimensional MRS may also have the potential to evaluate the proliferation activity of LGGs and identify potentially more aggressive clinical behavior.37 There is less convincing evidence, however, that MRS is sufficient for monitoring and follow-up of patients with suspected LGG.38 In some instances, MRS can also be used to discriminate radiation necrosis from tumor progression, as well as to monitor treatment progress.39
Among low-grade astrocytomas, measurement of relative cerebral blood volume (rCBV) derived from dynamic susceptibility-weighted perfusion contrast-enhanced MRI (DSC-MRI) correlates well with tumor behavior and patient survival.40 For these tumors, rCBV specifies regional tumor vascularity and expression of vascular endothelial growth factor (VEGF), two critical factors driving tumor growth.41 Most low-grade astrocytomas demonstrate slightly higher rCBV than normal tissue (1.5), with an increase in rCBV (1.75-2.0) indicating the evolution of a more aggressive tumor and often preceding the emergence of enhancement.42 Low-grade astrocytoma rCBV measurements also correlate well with time to progression, raising the possibility that DSC-MRI can predict the risk of transformation.43 In contrast, however, low-grade oligodendrogliomas have a paradoxically high rCBV, confounding the strict reliability of this modality for preoperative assessment. Similar MRI techniques such as quantitative analysis of whole-tumor gadolinium enhancement are also predictive of malignant transformation for likely the same reasons.44
Radiographic quantification of tumor metabolism cannot only identify malignant transformation in LGG,45 but it can also be employed to guide stereotactic biopsies. On positron emission tomography (PET) using fluorodeoxyglucose (18F-FDG), LGGs are hypometabolic, a feature that commonly distinguishes them from high-grade gliomas. In contrast, uptake of radiolabeled amino acids is increased in approximately two thirds of LGGs, and a prognostic role for amino acid PET in LGG has been proposed. O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is a new PET tracer that, in contrast to other amino acid tracers, fulfills all requirements for routine clinical application, similar to the widely used 18F-FDG. Accordingly, recent work indicates that baseline amino acid uptake on 18F-FET PET and a diffuse versus circumscribed tumor pattern on MRI are strong predictors for the outcome of patients with LGG.45 A comparable technique using 3′-deoxy-3′-18F-fluorothymidine (FLT), FLT PET, is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of LGGs.46
Surgery and the Value of Extent of Resection
In the past 2 decades, mounting evidence in the literature suggests that a more extensive surgical resection of LGG is associated with a more favorable life expectancy. In addition to providing longer overall survival, more aggressive resections for LGG can also influence the risk of malignant transformation, raising the possibility that a surgical intervention can alter the natural history of the disease.47 These associations are evident not only within the general hemispheric LGG population,19,48 but also for specific LGGs limited to certain subregions, such as insular LGGs.49,50 An overall review of the modern neurosurgical literature reveals 24 studies12,19,20,28,49,51–69 since 1990 that have applied statistical analysis to examine the efficacy of extent of resection in improving survival and delaying tumor progression among LGG patients. Six of these studies included volumetric analysis of extent of resection.12,28,49,57,60,70 Of the nonvolumetric studies, 15 demonstrated evidence supporting extent of resection as a statistically significant predictor of either 5-year survival or 5-year progression-free survival. These studies were published from 1990 to 2009 and most commonly employed a combination of multivariate and univariate analyses to determine statistical significance. Interestingly, of the three nonvolumetric studies that did not support extent of resection as a predictor of patient outcome, none of these reports evaluated progression-free survival, but instead focused solely on 5-year survival.
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