Brain Neoplasm, Glioblastoma

Jigisha P. Thakkar, M.D.

Definition

Glioblastoma (GBM) is the most aggressive diffuse glioma of astrocytic lineage and corresponds to grade IV in the World Health Organization’s (WHO) classification system. GBM is the most common brain and central nervous system (CNS) malignancy, accounting for 45.2% of malignant primary brain and CNS tumors, 54% of all gliomas, and 16% of all primary brain and CNS tumors.

GBM represents a molecularly heterogeneous disease with numerous subclassifications. GBMs comprise primary and secondary subtypes that evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. Primary (de novo) GBMs account for 80% of GBMs and occur in older patients (mean age 62 years). Secondary GBMs develop from lower-grade astrocytomas or oligodendrogliomas and occur in younger patients (mean age 45 years).

ICD-10CM CODES
C71.9	Malignant neoplasm of brain, unspecified

Epidemiology & Demographics

Incidence

Based on the 2014 CBTRUS report, the average annual age-adjusted incidence rate (IR) of GBM is 3.19/100,000 population.

Predominant Sex and Age

GBM is primarily diagnosed at older ages, with the median age of diagnosis at 64 years. It is uncommon in children, accounting for ∼3% of all brain and CNS tumors reported among infants to 19-year-olds. A higher incidence of GBM has been reported in men compared with women; the incidence rate is 1.6 times higher in males [3.97 versus 2.53]. Whites have the highest incidence rates for GBM compared with any other race in the U.S.

Risk Factors

Many genetic and environmental factors have been studied in GBM, but no risk factor that accounts for a large proportion of GBM has been identified. Like many cancers, the causes are sporadic. Factors associated with GBM risk are prior therapeutic radiation, decreased susceptibility to allergy, immune factors and immune genes, and some single nucleotide polymorphisms (SNPs) detected by genome-wide association studies (GWAS). There is no substantial evidence of GBM association with lifestyle characteristics such as cigarette smoking, alcohol consumption, drugs, or dietary exposure to N-nitroso compounds (cured or smoked meat or fish). Inconsistent and non-definitive results have been published regarding the risk of glioma with use of mobile phones.

Physical Findings & Clinical Presentation

Patients present with a variety of symptoms, including headache, seizures, symptoms of increased intracranial pressure, and cognitive disturbances.

Diagnosis

Imaging Studies

Initial workup includes imaging studies. Brain MRI with and without contrast is the study of choice, and demonstrates a contrast-enhancing tumor. Functional MRI is now used as an adjunct modality in perioperative planning for patients whose lesion is in vital regions (eloquent regions), such as those responsible for speech, language, and motor control. Pathologically, GBM is a high-grade astrocytoma characterized by hypercellularity, mitotic activity, nuclear atypia, pseudopalisading necrosis, and microvascular proliferation. Various molecular markers have been identified distinguishing GBM from other lower grade astrocytomas, as well as differentiating primary and secondary subtypes of GBM.

Treatment

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GBM is an aggressive neoplasm with a median survival of 3 months if untreated.
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Combined modality therapy with surgery, RT, and chemotherapy has significantly improved survival of GBM patients. Treatment is complex and initially consists of maximal-safe surgical resection followed by RT with concurrent temozolomide (TMZ) chemotherapy followed by six cycles of maintenance TMZ with tumor-treating fields.
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Surgical intervention has decompressive and cytoreductive effects, and there is increasing evidence of a significant survival advantage with complete resection.
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Various emerging treatment modalities under investigation seem promising, including immunotherapy. Regression of glioblastoma after chimeric antigen receptor T-cell therapy has been reported (see Brown CE, et al., in Suggested Readings).
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Symptomatic treatment includes corticosteroids to reduce cerebral edema, antiepileptic drugs for seizures, and painkillers for headache.

Referral

Treatment involves a multidisciplinary team approach including oncology, neurosurgery, neurology, and radiation oncology.

Prognosis

Survival: GBM has a poor prognosis with a low relative survival estimate; only a few patients reach long-term survival status of 2.5 years, and less than 5% of patients survive 5 years post-diagnosis. The relative survival for the first year after diagnosis is 35%, falls in the second year post-diagnosis to 13.7%, and continues to fall thereafter. Median survival of GBM post-diagnosis is 15 months following standard therapy. Several variables affect the prognosis of GBM patients, including age, preoperative performance status, tumor location, preoperative imaging characteristics of the tumor, and the extent of resection.
Prognostic molecular markers in GBM: All GBMs are WHO grade IV but exhibit significant genetic heterogeneity. Tumor subtypes, based on genetic alterations, exist within this larger homogeneous histologic category and carry prognostic significance. These markers include methylation status of the gene promoter for O⁶-methylguanine-DNA methyltransferase (MGMT), isocitrate dehydrogenase enzyme 1/2 (IDH1/2) mutation, epidermal growth factor receptor (EGFR) overexpression and amplification, tumor protein (TP53) mutation, ATRX mutation and genetic losses of chromosomes.
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  Primary GBMs show EGFR overexpression, phosphatase and tensin homolog gene (PTEN) mutations, and loss of heterozygosity (LOH) 10q, p16 deletions; less frequently shown are mouse double-minute 2 (MDM2) amplification, high frequency of telomerase reverse transcriptase (hTERT) promoter mutations, and absence of IDH1 mutation.
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  The hallmark of secondary GBMs is TP53, alpha thalassemia/mental retardation syndrome X-linked (ATRX) and IDH1 mutations; additionally, they show LOH 10q.
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  The MGMT promoter is methylated in approximately 50% of newly diagnosed GBMs. MGMT methylation is more common in secondary than primary GBM (75% versus 36%, respectively) and has prognostic and predictive significance of better overall survival in patients with GBM, irrespective of treatment choices.
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  IDH1/2 mutations are far more common in grades II and III astrocytomas and oligodendrogliomas compared with GBMs, and more than 90% of the mutations involve IDH1. IDH1/2 mutations are a selective molecular marker of secondary GBMs, help distinguish them from primary GBMs, and are a marker of more favorable prognosis in high-grade gliomas.
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  In GBMs, EGFR signaling promotes cell division, tumor invasiveness, and resistance to radiation therapy (RT) and chemotherapy. About 40% of all GBMs have EGFR amplification, and it is more common in primary as compared with secondary GBMs.
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  Mutation of the TP53 gene has been found in 60% to 70% of secondary GBMs and 25% to 30% of primary GBMs, and it occurs more frequently in younger patients. Studies of TP53 mutations as a prognostic marker have not been definitive.
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  ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary GBMs (57%), but is infrequent in primary (4%) and pediatric GBMs (20%) as well as pure oligodendroglial tumors (14%). In a prospective cohort of patients with astrocytic tumors, those harboring ATRX loss had a significantly better prognosis than the ones that expressed ATRX and had IDH mutation.
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  TERT mutation is one of the most frequent genetic alterations in primary adult GBMs and is significantly higher in these tumors as compared with secondary adult or any pediatric GBMs. GBMs with TERT mutation have a shorter survival than those without TERT mutations. However, when adjusted for GBM subtype (primary and secondary), they do not have a significant impact on survival.