Fast Facts: Glioblastoma

New molecular concepts pave the way for advances in diagnosis and treatment

M. McNamara, S. Brandner, S.C. Thust

• Publisher: S. Karger
• Year: 2020
• ISBN:
  9781912776719
• Topic: Medicina
• Subtopic: Hematología

Glioblastoma (also known as glioblastoma multiforme) is a malignant intrinsic tumor thought to arise from populations of stem/progenitor cells in the brain. It is the most common aggressive intrinsic brain tumor in adults, with the potential to spread rapidly within the brain. Patients with glioblastoma face a poor prognosis, with median overall survival of approximately 15 months. However, our growing understanding of the molecular biology of gliomas means that this outlook may be improving. The identification of clinically relevant subgroups defined by specific genetic mutations is challenging the traditional delineation between low- and high-grade gliomas that has been based on histological appearance and imaging. Indeed, it is becoming clear that, as a molecular entity, a glioblastoma, which by traditional classification is a grade IV glioma, may present with a lower grade initially and then become more aggressive – an important addition to the established concept. The care of a patient with a glioblastoma requires a coordinated approach delivered by a multidisciplinary team, with the aim of maintaining quality of life for as long as possible. Here, we provide a concise overview of the diagnosis and management of glioblastoma, as well as discussion of our emerging understanding of the molecular drivers that are helping us to delineate different patient subgroups. These subgroups will, hopefully, allow more targeted treatments in the future. This resource will be of interest to all those involved in caring for patients with this aggressive brain tumor, including neurologists, neurosurgeons, neuro-oncologists, radiation oncologists, palliative care specialists, specialist nurses and medical students. Contents: • Epidemiology, pathophysiology and classification • Clinical presentation • Diagnosis • Management • Treatment of associated conditions • Emerging research and treatment

1	Epidemiology, pathophysiology and classification

Glioblastoma is the most common intrinsic malignant brain tumor in adults. Specifically, it is a type of infiltrating glioma. Gliomas are part of a larger group of intrinsic tumors, which include ependymomas, embryonal tumors (e.g. medulloblastoma) and benign glioneuronal tumors (e.g. ganglioglioma) (Figure 1.1).

Figure 1.1 Simplified schematic of glial and other intrinsic high- and low-grade tumors. It is an overview only and is not comprehensive. Glioblastoma (WHO grade IV) is a high-grade glioma. There are other types of glioma, ranging from higher to lower grades. Other tumors of intrinsic origin, but not classified as gliomas, are shown in the purple area on the right. AT/RT, atypical teratoid rhabdoid tumor; DNET, dysembryoplastic neuroepithelial tumor.

Epidemiology

Incidence. The worldwide incidence of intrinsic brain tumors (benign and malignant) is an estimated 26 per 100 000 person-years,¹ while the overall age-adjusted incidence of gliomas ranges from 4.67 to 5.73 per 100 000 people.² Incidence varies widely by histological type, age, sex, race and country.

Glioblastoma is the most common malignant brain tumor and most common subtype of glioma.³ The age-adjusted incidence of glioblastoma ranges from 0.59 (in Korea) to 3.69 (in Greece) per 100 000 people. In the USA, the incidence is 3.21 per 100 000.^2,3 Its incidence increases with age (the median age at diagnosis is 65 years); it is uncommon in children. Given the aging populations in most western countries, the incidence of glioblastoma is expected to increase. It is most common in white men.^2,3

Location. Glioblastomas can occur anywhere in the brain or spinal cord, but in general are diagnosed in the cerebral hemispheres. The anatomic location influences both prognosis and treatment options. Gliomas have been found in the frontal lobe in 40% of cases, temporal in 29%, parietal in 14% and occipital in 3%, with 14% in deeper structures.⁴

Mortality. Glioblastomas are fast growing, and as such have a poor prognosis; indeed, glioblastoma has the worst prognosis of all glioma diagnoses. In the USA, the 5-year survival rate is 19.6% in children under 14, 22.7% in 15–39 year-olds and 4.3% in adults over 40; across all ages the 5-year survival rate is 5.6%.³ Survival rates in other countries follow a similar pattern.

Risk factors. Many genetic and environmental factors have been studied in relation to glioblastoma, but no key cause has been identified.

Environmental factors. Therapeutic radiation to the central nervous system or head has been shown to increase the risk of developing glioblastoma. Likewise, a high socioeconomic status has been associated with glioblastoma diagnosis.⁵ Large studies have failed to show an association between mobile phone use and the development of gliomas.⁶ Conversely, increased susceptibility to allergies has been shown to have a protective effect against glioblastoma. This may be due to an improvement in immune function.⁵ Short-term use (< 10 years) of anti-inflammatory drugs has also been shown to have a protective effect against glioblastoma, particularly in individuals with no history of allergies or asthma.⁵ It should be noted that these findings are from large retrospective case–control analyses, and prospective studies would be needed to confirm these results.

Genetic factors. Molecular studies have identified key genetic mutations associated with glioblastoma (see page 11). In rare cases (< 1%), glioblastoma occurs in people with genetic syndromes such as neurofibromatosis type 1, Turcot syndrome and Li Fraumeni syndrome, all of which have an autosomal dominant inheritance.⁷

Pathophysiology

Glioblastomas are malignant intrinsic tumors that are thought to arise from populations of stem/progenitor cells in the brain (Figure 1.2).

Tumors arise as a result of a driver mutation in a cell of origin (e.g. astrocyte, oligodendrocyte), which defines the location of the tumor, and occur during a preferred developmental period (e.g. childhood versus adult). Over the past 10 years the combination of location, age and mutation has been used to define many brain tumors (see Classification by genetic mutation, page 11).

Histological grading

The terms ‘low grade’ and ‘high grade’ derive from the histological appearance of a tumor tissue section stained with hematoxylin (which stains nuclei dark purple) and eosin (which stains cell bodies, processes and the tumor matrix pink). The World Health Organization (WHO) grading system takes into account these histological features and survival.^8,9

•Low-grade tumors (WHO grades I and II) have a low cell density, few or no mitotic figures, homogeneous nuclear shape and size (‘monomorphic’) and no necrosis (Figure 1.3a).

•Sometimes tumors that appear to be low grade on histology can have the molecular features of high-grade tumors. In the past, these tumors – which underwent biopsy before the histological high-grade features appeared – were misdiagnosed as low-grade tumors (Figure 1.3b).

•High-grade tumors (WHO grades III and IV) are more cellular and have mitotic figures and greater variability in nuclear shape and size (‘pleomorphic’). There is often necrosis, and stimulation with growth factors results in abnormalities in tumor blood vessels (see Figure 1.3c).

Figure 1.2 Gliomas originate from populations of stem/progenitor cells in the brain, shown here in the neurogenic zone beneath the lateral ventricles (subventricular zone; SVZ). Pockets of slowly dividing stem cells in the SVZ give rise to fast-dividing transient amplifying cells, which then differentiate into neural and glial precursors. These eventually become neurons, astrocytes and oligodendrocytes. A growth-promoting mutation, such as EGFR or PDGFR amplification or IDH mutations, turns stem or transient amplifying cells into cancer cell precursors, which acquire additional mutations to become cancer cells. Fully formed tumors are thought to harbor a population of cells with stem-cell-like properties (slowly dividing) which replenish the tumor bulk (cancer stem cell concept). In gliomas, these cells are known as glioma stem cells or glioma-initiating cells. Light tones indicate slowly dividing cells; dark tones indicate fast-dividing cells.

With the advent of molecular classification, the terms ‘primary’ (used to define the 95% of glioblastomas that manifest rapidly without evidence of less malignant precursor lesions) and ‘secondary’ (used to define the 5% of glioblastomas that develop from lower-grade gliomas) are becoming obsolete. Instead, the histological term ‘glioblastoma’ comprises several distinct biological entities, underpinned by combinations of genetic mutations and cells of origin, which are described in more detail below. Strikingly, no specific histological features set the distinct molecular entities apart.¹⁰

Classification by genetic mutation

The recognition of genetic mutations has largely superseded the importance of histological appearance in the classification of glioblastomas (see Figure 1.3). The key mutations and tumor subtypes are described below; Table 1.1 (see page 16) summarizes the molecular subtypes, their mutations, locations and age d...