Introduction

The World Health Organization (WHO) classification of central nervous system (CNS) tumors is based on tumor histology and cellular origin and was established to provide a common classification and grading of human CNS tumors that is accepted and used worldwide. The WHO divides brain tumors into classes: neuroepithelial tumors, tumors of the cranial and paraspinal nerves, tumors of the meninges, lymphomas and hematopoietic neoplasms, and germ cell tumors and tumors of the sellar region.¹ The different histologic types of CNS tumors are shown in Table 66-1. Meningiomas, glioblastomas, and astrocytomas constitute more than half of all CNS tumors. The frequency of different histologic tumor types varies with age, as shown in Figure 66-1. The incidence of all brain tumors is highest in the 75- to 84-year-old group. The incidence of meningiomas increases with increasing age, whereas for gliomas and pituitary adenomas, the incidence increases with age but then declines at the highest age category (see Fig. 66-1, A). Certain histologic types, such as germ cell tumors, medulloblastomas, and pilocytic astrocytomas, are far more common in children than in adults (Table 66-2; See Fig. 66-1, B).

For most patients with primary CNS tumors, surgery usually is the initial therapy. Radiation therapy is often an important component of treatment after surgery, but for management of malignant disease, chemotherapy has an expanding role. A great deal of knowledge has been amassed during the past two decades regarding the biology of brain tumors that should lead to improved treatments in the near future.

Epidemiology

An estimated 66,290 new cases of primary CNS tumors were expected to be diagnosed in the United States in 2012.² Approximately 22,910 of these tumors were expected to be malignant, representing 1.4% of all primary malignant cancers diagnosed in the United States.³ Malignant CNS tumors were expected to cause approximately 13,700 deaths in 2012.³

On the basis of data provided by the Surveillance, Epidemiology, and End Results (SEER) Program, Deorah and colleagues⁴ found that the incidence of brain cancer increased until 1987, when the annual percentage of change reversed direction. Elderly persons experienced an increase in brain cancer until 1985, but their rates were stable thereafter. Overall, however, the incidence of glioblastoma has been increasing, with survival only modestly improved during the past decade.⁵

Ionizing radiation is one of the few factors shown to have a strong association with the development of brain tumors. Exposure to ionizing radiation represents the most important exogenous risk factor for childhood brain tumors. Prenatal diagnostic x-ray exposure increases the risk of childhood brain tumors,⁶ and various reports describe the occurrence of gliomas, meningiomas, and other brain tumors in children who received radiation therapy to the head for tinea capitis and for prior malignancies.^7–10 A dose of 1 to 2 Gy of radiation, which was used to treat tinea capitis in Israeli children, was associated with an increased risk of the development of brain tumors—specifically, meningiomas, gliomas, and nerve sheath tumors.¹¹ A dose-response correlation in the induction of brain tumors was seen, with a relative risk of 3.0 at a dose of 1 Gy. Tumors developed at least 6 years after irradiation, with a mean interval greater than 15 years. Even lower doses of radiation delivered with radium-226 that were used to treat hemangiomas in Swedish infants (with a mean dose to the brain of 7 cGy) were found to be associated with an excess risk of intracranial tumors, including pituitary adenomas, gliomas, meningiomas, and nerve sheath tumors.¹²

A large amount of data has been accumulated on the incidence of brain tumors in patients who received cranial irradiation for the treatment of acute lymphoblastic leukemia (ALL). The estimated cumulative risk of secondary malignant brain tumors after childhood ALL therapy is 0.5% at 10 years after completion of therapy.¹³ In a study from St. Jude Children’s Research Hospital, the actuarial 20-year probability of developing a brain tumor in these patients was 1.4%.¹⁴ The probability of developing a high-grade glioma was greater in children younger than 5 years of age at diagnosis than in those 6 years of age or older (1.08% vs. 0.45%; P = 0.045). An apparent dose-response correlation was observed: the 20-year risk of developing a brain tumor was 3.2% in patients who received greater than 30 Gy, versus 1.03% in patients who received 21 Gy or less (P = .015). No CNS malignancies were seen in patients who did not receive cranial irradiation. The latency between irradiation and the diagnosis of a brain tumor ranged from 5.9 to 29 years (median, 12.6) but was longer for meningiomas (median, 19 years) than for high-grade gliomas (median, 9.1 years). Very similar results regarding the frequency of brain tumors, latency, and dependence on prior cranial irradiation were seen in studies from the German Berlin-Frankfurt-Munster group¹⁵ and the Children’s Cancer Study Group.¹⁶ The types of brain tumors that have been reported in these series include gliomas, meningiomas, and medulloblastomas. Patients who received cranial irradiation for ALL also often received intrathecal chemotherapy. It has been suggested that cranial irradiation and intrathecal chemotherapy may work synergistically to increase the incidence of glial tumors.^17,18

Viruses can induce brain tumors in animals in the experimental setting; however, no conclusive data point to viruses as a cause of brain tumors in humans (reviewed by Berleur and Cordier¹⁹). The relationship of human cytomegalovirus (HCMV) and gliomas remains controversial. The HCMV and gliomas symposium held in April 2011 resulted in consensus that sufficient evidence exists to conclude that HCMV viral gene expression exists in most, if not all, malignant gliomas and that HCMV could influence the phenotype of malignant gliomas by interacting with signaling pathways.²⁰ Other authors who have used the Cytomegalovirus Seroprevalence in the United States data from the National Health and Nutrition Examination Surveys, 1988-2004, have concluded that a possible CMV-glioblastoma association could not be corroborated with CMV seropositivity rates.²¹

Also lacking is conclusive evidence that occupational exposure to industrial chemicals leads to the development of brain tumors, although a number of studies have suggested such a link (reviewed by Wrensch and coworkers²²). Some of the chemicals that can induce brain tumors in laboratory animals, such as polycyclic aromatic hydrocarbons, can do so only when administered by direct contact or transplacentally, but not by inhalation or dermal contact; the latter two modes of exposure are more relevant in the occupational setting. Specific chemicals that have been examined include cosmetics containing N-nitroso compounds, organic solvents, chemicals used in the manufacture of synthetic rubber, formaldehyde, phenols, polycyclic aromatic compounds, polyvinyl chloride, and pesticides. Although many chemicals can induce brain tumors in laboratory animals, no definitive associations have been found in humans. For example, N-nitroso compounds, which commonly are present in foods, are known to be neurocarcinogenic in animals. Oxidants in the environment can cause DNA damage, so it has been hypothesized that antioxidants, such as vitamin E, found in certain foods may protect against the development of cancers. Epidemiologic studies, however, have provided mixed support for the idea that the intake of N-nitroso compounds, antioxidants, or specific nutrients in foods can influence the risk of developing brain tumors.¹⁹

Vinyl chloride can induce brain tumors in rats; however, a recent review found that the association in humans is inconclusive.²³

Recently a great deal of interest has emerged in a possible association between the use of cell phones and the risk of brain tumors. In a case-control study, Inskip and coworkers were unable to show a correlation between the duration of cell phone use and the development of gliomas, meningiomas, and acoustic neuromas.²⁴ Other large case-control studies also have failed to find any association between cell phone use and the risk of developing brain tumors.^27–27 A metaanalysis of 9 case-control studies revealed no increased risk in analog or digital cellular phone users.²⁸ Nevertheless, some still claim that there is a link between cell phone use and brain tumors.²⁹ Additionally, the International Agency for Research on Cancer (IARC), a WHO agency, has classified radiofrequency electromagnetic fields as “possibly carcinogenic to humans.”³⁰

Other factors that have been analyzed for their possible relationship to the development of brain tumors include a history of head trauma and injury, drugs and medications, allergies, seizures, smoking and alcohol consumption, and exposure to power-frequency electromagnetic fields. None of these factors, however, has been conclusively shown to be important (reviewed by Wrensch and associates²²).

Most brain tumors represent sporadic cases; however, familial clustering has been noted. It is estimated that hereditary syndromes account for 2% of childhood brain tumors, although this may be an underestimate because hereditary syndromes may be undiagnosed in a number of cases.³¹ Some hereditary syndromes known to be associated with brain tumors are listed in Table 66-3 (reviewed by Kimmelman and Liang³²). Some of the associations are extremely strong. Nearly 70% of all optic pathway gliomas occur in patients with neurofibromatosis type 1 (NF1), and acoustic neuromas commonly occur in patients with NF2. In addition, hereditary immunosuppression disorders such as Wiskott-Aldrich syndrome, as well as treatment-associated immunosuppression as in organ-transplant recipients, or exogenous immunosuppression as in human immunodeficiency virus (HIV) infection, are known to be associated with an increased risk of primary CNS lymphoma.

Normal cells rely on growth factors secreted in their local environment to stimulate their growth. However, many CNS tumors have developed the ability to express their own growth factors along with the respective receptors, resulting in an autocrine loop that allows for self-stimulation.³³ Platelet-derived growth factor receptor–α (PDGFR-α), for example, is overexpressed in all grades of astrocytomas, but only higher-grade tumors overexpress the ligands PDGFA and PDGFB.³⁴ Insulin-like growth factors and their receptors both are expressed in brain tumors, including gliomas and meningiomas.³⁵ The epidermal growth factor receptor (EGFR) is amplified or overexpressed in 50% of glioblastomas,³³ and expression of transforming growth factor–α (TGF-α), a ligand that binds to this receptor, is increased in many gliomas.^36,37 Both scatter factor (also known as hepatocyte growth factor) and its receptor c-Met are expressed in gliomas, with the highest level of expression seen in the most malignant tumors.³⁸

As a result of increasing expression of receptors and ligands, increased signaling occurs in many brain tumors, resulting in activation of many different pathways that are important in proliferation (reviewed by Rao and James³⁶). The best studied of these pathways is the microtubule-associated protein kinase (MAPK) pathway, which involves Ras and Raf. Another pathway that has attracted much attention recently is the phosphoinositide-3 (PI3) kinase pathway, which leads to activation of Akt. Mutation of PTEN, which occurs in 30% to 40% of glioblastomas, also can lead to increased Akt activation.³⁹

Ras activation commonly is seen in human astrocytomas and neurofibromas despite the fact that these tumors rarely contain Ras mutations. In astrocytomas, Ras activation probably occurs through activation of growth factor receptors such as EGFR and PDGFR.⁴⁰ Other mechanisms of activation of aberrant G proteins have been identified in other CNS tumors (reviewed by Woods and co-workers⁴¹). In NF1, loss of expression of neurofibromin, an inactivator of Ras, is seen (see Table 66-3). This loss of neurofibromin leads to the increased Ras activation seen in NF1-associated astrocytomas. Pituitary adenomas often show activation of the α subunit of the large heterotrimeric Gs protein, resulting in mitogenic signaling.

The Wnt pathway has been shown to play a role in glioma tumorigenesis. Investigators have shown that the Wnt-specific secretory protein Evi is overexpressed in astrocytomas.⁴² Furthermore, the same researchers showed that the depletion of this protein in glioma cells leads to decreased cell proliferation and apoptosis. Additionally, silencing of Evi in glioma cells leads to reduced cell migration and the ability to form tumors in vivo.⁴² Involvement of Wnt/β-catenin signaling in gliomas has been reviewed by Zhang et al.⁴³

Cell proliferation is intimately tied to cell cycle regulation. Mutations in the p16/Cdk4 or Cdk6/cyclin D/Rb pathway or the p21/p53/Mdm2/p19^ARF pathway are common in many brain tumors, particularly gliomas.