Synonyms

Neoplasm

Definition

A brain tumor is a mass of abnormal cells. There are two broad categories of brain tumors. Primary brain tumors arise from an abnormal proliferation of cells within the central nervous system (CNS). In contrast, metastatic tumors originate elsewhere in the body and spread to the brain and are therefore “malignant” (Blumenfeld 2010). Brain tumors that are “malignant” usually grow rapidly, are life threatening, and have the potential to spread and infiltrate the CNS (Blumenfeld 2010). Brain tumors are thought to be “benign” if they are slow growing, have distinct borders, and do not infiltrate or disseminate widely within the CNS (Blumenfeld 2010). This entry will focus on primary brain tumors and will overview classification, types, incidence, etiology, symptoms (including cognitive disorders), treatments, and prognosis, with particular reference to older adults.

Classification of Brain Tumors

The World Health Organization (WHO) classification of tumors of the central nervous system (Louis et al. 2007a) is a way of grading the biological behavior or “malignancy.” The WHO grading system is based on the microscopic appearance. WHO grade can be a key factor influencing the choice of therapies, particularly the use of specific chemotherapy and radiation protocols (Louis et al. 2007b; Du Plessis 2005). Grade I applies to tumors with low proliferation potential and the possibility of “cure” following surgical resection alone. Grade II usually applies to tumors that are generally infiltrative and can recur, despite low-level proliferation, and some progress to higher grades of malignancy. Grade III tumors are actively reproducing abnormal cells; they infiltrate adjacent normal brain tissue and tend to recur, often as a higher grade. Grade IV tumors are very abnormal and reproduce rapidly, forming new blood vessels to maintain rapid growth (Louis et al. 2007a, b).

Box 1: Overview of World Health Organization (WHO) Tumor Classification System

  • Grade I: Tumors with low proliferation potential

  • Grade II: Infiltrative tumors with potential for low-level proliferation

  • Grade III: Infiltrative and actively growing tumors that tend to recur

  • Grade IV: Highly abnormal and rapidly growing tumor

Types of Brain Tumor

The most common type of primary malignant brain tumor, accounting for around 70–80% of patients, is malignant glioma (Omuro and DeAngelis 2013; Cancer Council of Australia 2011). Within the malignant glioma group, the following types and WHO grades have been identified: astrocytoma (WHO Grade I-IV), oligodendroglioma (WHO Grade II-III), ependymomas (WHO Grade I-II), mixed oligoastrocytomas, and other rarer forms (as summarized in Table 1). Astrocytomas grow from glial cells and grow slowly or rapidly. Oligodendrogliomas grow from cells that insulate the nerves (oligodendrocytes). Glioblastoma multiforme or “GBM” (also astrocytoma Grade IV) commonly contains a mix of cell types and is highly malignant. At present, with the advent of new technologies such as next-generation sequencing and proteomics, the classification of malignant gliomas is changing as more information about the molecular changes occurring at each step of the tumorigenesis process comes to light (McKay 2014).

Brain Tumors in Older Adults, Table 1 Abridged summary of the main categories of WHO Classification System (2007) for central nervous system tumors. The most common types in older age groups (>55 years) are indicated in bold (Dolecek et al. 2012)
Full size table

Meningiomas are often WHO Grade I and benign. However, meningiomas can also be malignant, the latter tending to be of a higher WHO Grade (II or III) (Dolecek et al. 2012).

Incidence and Age

The median age at diagnosis for all primary brain and CNS tumors is 59 years, according to the 2005–2009 CBTRUS statistical report for the United States (Dolecek et al. 2012). With increasing age, meningiomas are the most common type of brain tumor diagnosed, followed by gliomas which peak in incidence at age 65–74 years (Dolecek et al. 2012; Wrensch et al. 2002). Meningiomas have a significantly higher incidence (3.5 times) in individuals >70 years, compared to <70 years.

Etiology

The causes of brain tumors remain elusive. However, there is a slightly higher risk with increasing age, being male rather than female and with exposure to ionizing radiation (Cancer Council of Australia 2011). Individuals with rare genetic conditions such as neurofibromatosis type 1 or 2 have a higher risk of developing a brain tumor than the general population (Cancer Council of Australia 2011). The molecular causes of malignant glioma are highly variable between individual patients, even within each subset (Omuro and DeAngelis 2013). In the case of malignant gliomas, such as astrocytomas and oligodendrogliomas, it is characteristic for multiple cell changes to be present at the molecular or DNA level. These may include chromosomal aberrations, single DNA base substitutions of mutations, DNA methylation, or epigenetic modifications. Recently, changes in gene activity that are not caused by changes in the DNA sequence, or epigenetic alterations, have been linked to the formation of cancer (McKay 2014).

Symptoms and Diagnosis

The presenting symptoms of a primary brain tumor are determined by several factors including the tumor’s size, location, and rate of growth. Common symptoms include headache nausea/vomiting, changes in cognition and personality, gait imbalance, urinary incontinence, hemiparesis, aphasia, hemi-neglect, visual field defect, and seizures (Omuro and DeAngelis 2013; McKay 2014).

Headaches are relatively frequent, presenting in about 50% of patients at diagnosis, but usually with a nonspecific pain pattern, progressive severity, and unilateral localization. In an individual older than 50 years, a new-onset headache may be indicative of a tumor-associated headache from a benign headache. However, the likelihood of a brain tumor being the underlying cause of headaches is less than 1 in 1000, and new-onset seizures also has extremely low predictive value for indicating the presence of a tumor, being <2% (McKay 2014). Nevertheless, as one example, the current Australian guidelines recommend that a patient with new-onset seizures or recurrent headache uncharacteristic for that patient should undergo brain imaging to establish the cause, particularly if focal neurological symptoms such as dysphasia, hemiparesis, or hemianopia are present (McKay 2014).

Neurological Signs

Changes or disturbance to cognitive functions, or “thinking skills,” may develop as a result of brain tumors. Cognitive functions allow an individual to respond to both the demands of the environment and also to their own internal desires and needs. Cognitive skills include the ability to speak, concentrate, remember, reason, reflect, perceive, and understand. Cognitive disorders can occur when the brain is damaged or disrupted, for example, with growth of a brain tumor. Changes in cognitive functions can be interpreted as “personality changes” or can be mistaken for psychiatric disorders or dementia, particularly in older adults (Cancer Council of Australia 2011; McKay 2014). Cognitive difficulties may be a presenting symptom or they may arise during or after treatments such as surgery, radiation, or chemotherapy (see below for further details of cognitive changes).

Focal neurological signs such as hemiparesis, sensory loss, or visual field disturbances are common and typically indicate the tumor location in the brain. Other neurological signs that arise usually in larger tumors that cause mass effect or displacement within the brain include gait imbalance and incontinence.

Brain Imaging

Imaging of brain tumors is first to diagnose or confirm a suspected diagnosis. Secondary to this is precise localization and characterization to inform further treatment and/or management (Cancer Council of Australia 2011). Computed tomography (CT) and magnetic resonance imaging (MRI) are currently the main brain tumor diagnostic imaging techniques.

MRI has largely replaced CT scanning in the management of patients with brain tumors, with CT only used in initial imaging and in monitoring acutely changing neurological symptoms. When evaluating non-enhancing tumors, MRI has the benefit of being more specific and sensitive than CT. MRI imaging modalities include MR spectroscopy, perfusion imaging, and diffusion scanning. These MRI techniques are beneficial in differential diagnosis of high-grade gliomas, such as anaplastic astrocytoma and anaplastic ependymoma, primary CNS lymphoma, metastatic tumors, brain abscess, and other neurologic processes (McKay 2014). Although both MRI and CT imaging techniques reveal structural information, they are limited in providing information about the tumor itself in terms of biology and activity.

Molecular imaging with positron emission tomography (PET) has recently been used in brain tumors. PET provides the ability to ascertain additional metabolic information that can be helpful for patient management as well as for evaluating the indication of other therapeutics (McKay 2014). For example, there are several benefits to using PET with radiolabeled glucose and amino acid analogues such as MET or 11C-methionine. In particular, this form of PET can help with the following: tumor diagnosis, differentiation between recurrent tumors and tissue death due to radiation, and guiding a biopsy or treatment. In recent years, fluorinated amino acid tracers such as FET, or [18 F] Fluoroethyl-l-tyrosine, have also been used to guide treatments including surgery in patients with primary brain tumors.

Prognosis

The survival time after treatment can vary and depends on several factors including tumor type and grade, location of tumor within the brain, gross total tumor resection, age, and general health preoperatively, which is often indicated by the Karnofsky Performance Status score (Chaudhry et al. 2013). However, negative predictors and generally poorer prognosis are indicated if an individual is older (>60 years), the tumor is high-grade, resection is incomplete, and the tumor location is crossing the midline or is within the periventricular region of the brain (Cancer Council of Australia 2011). Although recent advances in treatments using combined chemotherapy and radiation, post-resection (Stupp et al. 2005), suggest increased survival, in general, glioblastoma multiforme (GBM) has the poorest survival in all age groups. Further, within any brain tumor type, older adults have poorer survival rates than younger individuals (Wrensch et al. 2002).

Treatments

The approaches to primary and metastatic brain tumor treatment are based on the histology and grade of the tumor, as well as the age and medical condition of the patient. The options for treatment include surgical resection, radiation, and chemotherapy either alone or in combination. In addition, for some tumor types or depending on a patient’s general condition and age, a conservative approach of “watch and wait” is taken (Rosenfeld and Pruitt 2012). Although not yet a standard practice, increased knowledge about the molecular biology of tumors, the microenvironment of tumors, and immunologic interactions and how these relate to treatment response will lead to new personalized treatment regimes (Omuro and DeAngelis 2013; Rosenfeld and Pruitt 2012).

An important factor in improving brain tumor patient outcomes is receiving centralized care with a team of specialized health professionals (McKay 2014), which is similar to the benefit of care in an organized and centralized stroke unit when compared to a decentralized team. For primary brain tumors, analysis of surgical resections or biopsies identified that large-volume centers had lower postoperative mortality rates than centers with smaller numbers of patients.

Surgery

Surgical resection is often the first line of medical management for benign and malignant tumors, including meningiomas and gliomas that are the most common types in older adults. Thus, for benign meningiomas tumor, resection is standard, and for higher WHO grade II and III meningiomas, surgical resection and postoperative radiation therapy are recommended to increase the likelihood of reducing recurrence rates. For more aggressive high-grade gliomas, resection with combined radiation and chemotherapy has become a standard care.

In adults over the age of 60 years, surgical resection of meningiomas carries with it a higher risk of mortality and morbidity compared to intracranial tumor surgery in general (Konglund et al. 2013). Specifically, a large study of inpatients following tumor resection (N = 8861; 26% older persons >70 years) revealed a marked effect of older age on each of the primary outcomes. Thus, inpatient mortality rate was higher in the older patients, as well as discharge rates to a facility other than home, and older persons were more likely to have a longer inpatient hospital stay (Bateman et al. 2005). In addition, postsurgical complications in older adults have been reported to include hematomas, deep vein thrombosis, and neurological symptoms. Although the medical management for patients with life-threatening tumors is clear in that surgical resection is necessary, the increased risk of complications for individuals >70 years must be weighed against the expected positive outcomes (Bateman et al. 2005). The benefits of meningioma resection can be measured in terms of improved cognitive function on neuropsychological tests and adequate quality of life, as measured by functional independence scales like the Karnofsy performance scale (Konglund et al. 2013).

Radiation and Chemotherapy

For malignant brain tumors such as glioblastoma, radiation therapy is the treatment of choice. Whole brain radiation has been commonly used until the last decade during which time the use of stereotactic radiosurgery (SRS) has become increasingly common. The advantage of stereotactic radiosurgery is that, via this image-guided method, a precise radiation dose can be delivered, which has the potential to reduce treatment time and toxicity. Moreover, preservation of neurocognitive function is more likely with targeted rather than whole brain radiation.

As noted above, the current standard of care for the medical management of primary brain tumors and in specifically glioblastoma includes radiation treatment combined with the alkylating agent temozolomide (TMZ), followed by 6 months of adjuvant TMZ (McKay 2014; Stupp et al. 2005). In a 2005 clinical trial, this regime was found to significantly prolong survival (Stupp et al. 2005). However, the benefit of TMZ is fairly modest with a median overall survival 12.1 months for radiation treatment alone compared to 14.6 months for radiation combined with TMZ (Stupp et al. 2005; Quant and Wen 2010). New therapies, including immunotherapy, vaccines, and the use of nanoparticles, are emerging methods of medical management.

Immunotherapy

A relatively recent therapy is based on the role of immune cells in regulating tumor progression. Each tumor has its own unique set of genomic and epigenomic changes, which can influence the host immune response to tumor. Active immunotherapy relies on stimulation of the patient’s immune system to increase the immune response to target tumor cells. To this end either the entire immune system can be boosted or the immune system can be trained to attack the tumor (McKay 2014). McKay and Hadfield recently summarized the three broad categories of immunotherapy strategies:

  1. (i)

    Immune priming (active immunotherapy), or sensitization of immune cells to tumor antigens using various vaccination protocols

  2. (ii)

    Immunomodulation (passive immunotherapy), which involves targeting cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells

  3. (iii)

    Adoptive immunotherapy, which involves harvesting the patient’s immune cells, followed by activation and expansion in the laboratory prior to reinfusion

Although this line of treatment is potentially valuable, it has been hampered by factors such as the blood–brain barrier and lack of lymphatic drainage in the brain (McKay 2014).

Cognitive Disorders: Detection, Assessment, and Management

Changes in thinking, behavior, or emotion are quite common in primary and metastatic brain tumors. This section will give an overview of the importance, causes, and types of cognitive disorders and current methods for detection, with examples of practical tips for managing cognitive difficulties.

Cognitive function is an independent prognostic factor in the survival of glioma patients (Taphoorn and Klein 2004). Moreover, cognitive assessment is useful for several reasons: to inform clinicians of areas to target for neurorehabilitation; to monitor progress and facilitate decision-making about further intervention; if there has been a decline in cognitive function, to ask whether the tumor has recurred or progressed; and if there are subtle alterations in cognitive function, to address whether these are significant or not, particularly when monitoring slow-growing low-grade gliomas (Robinson et al. 2015).

Disturbance to cognitive function in the context of a brain tumor can be due to the location and size of the tumor, prognosis (benign or malignant and WHO grade), treatment (surgery, radiation, chemotherapy), secondary medical complications of treatments, and also an individual’s psychology response (anxiety, depression) (Cancer Council of Australia 2011).

Cognition and Aging

An additional factor in older adults is the nature of aging itself. With increasing age, there is a disproportionate loss of both white and gray matter particularly to the frontal regions of the brain (Resnick et al. 2003). The frontal cortex is associated with complex thinking and adaptive behavior also known as “executive functions.” In addition, age has been found to exacerbate executive dysfunction in patients with focal frontal lesions, such as a brain tumor in the frontal cortex (Cipolotti et al. 2015).

Overview of Cognitive Disorders

  • Aphasia and language: A disorder of language that can affect speaking (expressive aphasia) or understanding (receptive aphasia) or both (global aphasia). The most common language disorder affects the ability to retrieve words or names of objects, people, or places (nominal aphasia). In subtle forms of aphasia, an individual may have difficulty thinking of what they want to say (dynamic aphasia). Literacy and numeracy disorders are termed dyslexia when the problem is with reading, dysgraphia when the problem is with spelling, and dyscalculia when arithmetic difficulties are present.

  • Amnesia: This is a disorder of memory that can affect personal memories (autobiographical memory), learning new information (episodic memory) or general knowledge about the world (semantic memory). Amnesia can affect verbal or visual information (selective amnesia) or both (global amnesia).

  • Agnosia: This is a disorder of perception and can be present in any form of sensation (e.g., touch, taste, hearing, smell, and vision). The most common form is visual agnosia, that is, when someone does not recognize what they are looking at with their eyes or they have difficulty knowing exactly where something is in the surrounding environment.

  • Attention and concentration: Disorders of attention and concentration are common in any condition affecting the brain. Difficulties can be in focusing attention or in sustaining attention over time. Problems can manifest as distractibility or impulsivity.

  • Executive dysfunction: Executive functions are comprised of many different abilities, including problem solving, reasoning, decision-making, judgment, initiation of behaviors, monitoring and self-regulation of behaviors, abstract thinking, and strategic thinking. These skills can be disturbed separately or several executive functions may be affected. These are the abilities that enable an individual to adapt their behavior in order to respond and interact appropriately in any situation. The executive abilities are uniquely human and especially vulnerable to the aging process.

  • Speed of information processing: When information processing is disturbed, thinking can be slowed down and other cognitive skills can be affected as the amount of information processed may be limited.

Detection and Management of Cognitive Disorders

A significant issue in brain tumors is the method for detection of cognitive disorders. The most widely used method is cognitive screening tools such as the mini-mental state examination (MMSE) or the Montreal Cognitive Assessment (MoCA). However, recent studies have shown that, although the MoCA is better at detecting cognitive deficits than the MMSE, the MoCA fails to detect mild and/or focal cognitive deficits in patients with brain tumors (Robinson et al. 2015). This is particularly for attention, language, and executive functions. Thus, best practice is to assess cognitive disorders with a brief cognitive assessment that is tailored to a patient based on tumor location and presenting neurological and neuropsychological symptoms (Robinson et al. 2015).

Simple strategies can help minimize the impact of cognitive disorders. Detailed strategies can be obtained from specialists in neuropsychological rehabilitation. However, see Box 2 for simple handy tips when experiencing thinking problems.

Box 2: Examples of Handy Tips for Thinking Problems

  • Stimulation: Reduce background noise in the environment to limit the amount of information to be processed. For example, turn off the television or radio unless watching or listening to a program.

  • Memory: Use technological supports like a smartphone, calendar, or notebook to remember appointments and important information.

  • Fatigue: If easily fatigued, plan activity in “intervals,” i.e., activity interspersed with rest throughout the day.

  • Words: If names of people or things are difficult, ask someone to give the name (rather than guess), repeat it aloud, and/or write down important names.

  • Problem solving: When planning an activity or how to complete a complex task, break it down into steps and then order the steps and complete these.

General Summary

Age poses an increased risk of developing a primary brain tumor, from the age of 55 years but particularly for those over 65 years of age. The most common types of tumors in older adults are meningiomas and gliomas. Moreover, prognosis for survival is poorer if an individual is older than 60 years. In the context of aging, this is associated with an increased loss of brain volume in the frontal region, impacting complex thinking and adaptive behavior. Older adults are particularly vulnerable for tumors disrupting the frontal cortex. Thus, despite the rarity of primary brain tumors, older adults may experience more postsurgical complications, and they have a poorer prognosis for survival.