1
Central Nervous System Tumors

Mark R. Gilbert and Edina Komlodi-Pasztor

Introduction

Central nervous system tumors can be divided into primary brain tumors and metastatic lesions. This chapter will focus on the most frequently occurring questions related to tumors originating from the brain, spinal cord, or associated tissue. Primary central nervous system lymphoma is discussed in a separate chapter. We will review practical questions related to epidemiology, classification, and treatment of primary brain tumors. We will discuss the incidence rates and the genetic and environmental predisposing factors related to brain cancers. A brief overview of the new fifth edition of the World Health Organization (WHO) classification system will be provided. We will summarize treatment recommendations of the most commonly occurring benign and malignant primary brain tumors, such as meningioma, oligodendroglioma, astrocytoma, and glioblastoma.

1. How do we classify brain tumors?

Expert Perspective: Brain tumors can be divided into two main groups: benign tumors and malignant cancers. Malignant cancers can be further subdivided into metastatic lesions and primary central nervous system cancers (PCNSC).

Instead of using the tumor, node, and metastasis (TNM) staging system as in systemic solid tumors and hematologic malignancies, central nervous system (CNS) cancers are classified based on the World Health Organization (WHO) grading system. This grading system has been undergoing dynamic changes in the setting of new advances in molecular genetics. Although traditionally this grading system was based on histological features, the revised WHO classification published in 2016 used molecular parameters for the first time in addition to histology to categorize tumor tissues. The role of molecular diagnostics in CNS tumor classification is being further solidified in the 2021 WHO classification, which follows the recommendations of the 2019 cIMPACT-NOW Utrecht meeting (Louis et al. 2021).

As described in the new fifth edition of the WHO classification system, using a layered reporting structure, including integrated diagnosis, histological diagnosis, CNS grading, followed by molecular information, is recommended. The integrated diagnosis incorporates important molecular features in addition to tissue-based histological findings, highlighting the importance of different diagnostic modalities in the accurate diagnosis in CNS tumors. Brain and spinal cord tumors are graded from 1 to 4, where the higher numbers indicate faster growth and/or greater aggressiveness. Each tumor type has its own grading that represents its historically determined natural history but does not necessarily correlate with prognosis in this current era. For example, the five-year survival of a grade 3 meningioma is 64%, whereas almost all patients with a grade 4 WNT-activated medulloblastoma have long-term survival if treatment is provided. In recent years, molecular biomarkers became an important part of clinical care in neuro-oncology because they have promoted better categorization of CNS tumors. Consequently, the 2021 WHO classification enhances the use of molecular biomarkers to influence grading in many tumor types due to their powerful prognostic value. In addition, molecular biomarkers also have the potential to influence treatment in some cases. Imminent advances in molecular diagnostics are expected to further evolve the landscape of neuro-oncology soon.

2. What is the incidence of primary brain cancers?

Expert Perspective: Although CNS tumors (including malignant and non-malignant etiology) are the most common solid tumor types in children below age 14, they are less frequent in adults. Brain tumors are the 3rd most common tumor types in people between the ages of 15 and 39 with an average annual age-adjusted incidence rate of 11.54 per 100,000 population, and the 8th most common tumor type above age 40 with an average annual age-adjusted incidence rate of 42.85 per 100,000 population. In adults, 70.3% of brain tumors are non-malignant, and among them, meningioma is the most common tumor type (Table 1.1). Regarding adult malignant tumors, glioblastoma leads in frequency because it represents 14.5% of all brain tumors and 48.6% of malignant brain cancers. Malignant brain cancers are more prevalent in males than females (56% vs 44%, respectively). Gender differences are reversed in non-malignant cancers, where 36% of the cases occurred in males and 64% in females. Incidence rates for malignant primary brain tumors are highest in Whites (7.58 per 100,000), but non-malignant primary brain tumors are more common in Blacks (19.45 per 100,000) (Ostrom et al. 2020).

Table 1.1 Molecular characteristics and grading of the most frequently occurring CNS tumors in adults.

3. Do primary brain cancers have genetic predisposition?

Expert Perspective: Most adult primary brain tumors occur sporadically without an identifiable genetic predisposition. However, genetic susceptibility to brain cancers is suggested by tumor aggregation in families, genetic cancer syndromes, linkage analyses, and lymphocyte mutagen sensitivity. Thorough medical history taking with close attention to the family cancer history can reveal family cancer clusters and/or raise suspicion for a genetic syndrome associated with brain cancers. The most common genetic conditions associated with primary CNS tumors include Lynch syndrome, neurofibromatosis type 1, Li-Fraumeni syndrome, tuberous sclerosis (Table 1.2). In addition to colorectal cancer, endometrial cancer, upper urinary tract cancer, and ovarian cancer, patients with Lynch syndrome are at high risk of developing gliomas in their fifth decade. Patients with neurofibromatosis type 1 can develop optic pathway tumors in childhood and/or glioblastoma, as well as malignant peripheral nerve sheath tumors in early adulthood. They are also more prone to be diagnosed with breast cancer, endocrine cancers, sarcoma, melanoma, ovarian cancer, and prostate cancer. Patients with Li-Fraumeni syndrome can also develop multiple cancers, including solid tumors (breast cancer, osteosarcoma, sarcoma, and adrenocortical cancer), hematologic malignancies (leukemia), and CNS tumors (choroid plexus tumor in infancy, medulloblastoma in childhood, and high-grade glioma in early adulthood). Patients with tuberous sclerosis may develop subependymal giant-cell astrocytomas before age 25 in addition to other solid tumors (like rhabdomyoma and kidney cancer). Recognizing a genetic syndrome based on clinical signs and genetic markers is crucial to provide appropriate medical management. The identification of a genetic syndrome may influence the treatment plan because targeted therapy has been increasingly accessible for specific mutations. In addition to that, it may also guide future cancer surveillance and the need for family cancer screening. (See Chapters 45-47.)

Table 1.2 Characteristics of the most common genetic conditions associated with primary central nervous system tumors.

Neurofibromatosis

type 1

4. Do environment factors cause brain tumors?

Expert Perspective: The question of environmental factors leading to brain tumors has been extensively investigated, but there are only a few environmental factors that have been confidently linked to tumorigenesis in the CNS. Among these, therapeutic ionizing radiation has been uniformly accepted as a risk factor for brain cancers including meningiomas, gliomas, and nerve sheet tumors. This risk is even higher when radiation exposure occurs at young age. Although the significance of...