The following module was designed to supplement medical student’s learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, screening & testing, classification, signs & symptoms, diagnosis, radiology, pathology, staging, management and treatment of CNS cancer is provided. For quick reference, all objectives are answered in point form in the very last page of this module. summary tables are also placed at the end of every section.

By the end of the tutorial, the following objectives should be addressed:

1. Review the anatomy of the central nervous system
2. Describe what signs and symptoms arise from brain lesions based on location
3. State the incidence of gliomas and glioblastomas
4. State the risk factors for brain tumours
5. State the recommended screening procedure for brain tumours
6. State the routes of spread of CNS tumours, contrasting primary and secondary tumours
7. Understand the classification of CNS tumors By cell of origin, By location of cancer origin, By tumour histology and grade
8. Name the red flag signs of headache of possible neoplastic etiology
9. List the differential diagnosis of a brain mass
10. Describe an appropriate history and physical to be performed on a patient with suspected brain mass
11. Outline imaging techniques used in CNS tumours
12. Outline characteristic features seen on imaging of a high grade glioma
13. Describe biopsy techniques employed today and importance of biopsy in diagnosis
14. Describe the prognostic factors for brain tumours with emphasis on MGMT and IDH1/IDH2 , 1p19qLOHq, H3 (H3 K27, H3 G34) mutation implications
15. Describe the characteristic pathology of a high grade glioma
16. Describe what staging system is used for central nervous system tumours
17. Describe standard treatment protocol for high grade gliomas
18. Describe how treatment regimens may change for elderly patients
19. Describe what the recommended follow up protocol is after receiving treatment for a high grade astrocytoma

Brain tumours are a diverse group of neoplasms of different histologic type and growth rate, which can produce their signs and symptoms by local brain invasion, increased intracranial pressure, and compression of adjacent structures (1). While neoplasms of the central nervous system were previously regarded with pessimism, it is notable that over 50% of brain tumours are benign (2).

This module will provide an introduction to the clinical evaluation and treatment of glioblastomas, as an introduction to tumours of the central nervous system.  Glioblastoma, also known as Glioblastoma Multiforme (GBM), is classified by the World Health Organization as a subtype of Diffuse Astrocytoma, a tumour of neuroepithelial tissue. Other tumours of neuroepthelial tissue, or glial tissue, include oligodendroglial tumours, ependymal tumours, choroid plexus tumours and pineal tumours. These should be differentiated from tumours of other central nervous system structures, such as pituitary tumours and tumours of nerve sheaths or meningeal tissues (2). More information and clarification of classification will follow, this is simply presented to give readers the opportunity to orient themselves.

Neuroepithelial Tissue Tumour Classification (2)

1) Astrocytic Tumours:

• Diffuse Astrocytomas: Diffuse, Anaplastic, Glioblastoma
• Circumscribed Astrocytomas: Pilocytic, Pleomorphic

2) Oligodendroglial Tumours: includes Low Grade, Mixed, Anaplastic Oligodendroglioma

3) Ependymal Tumour: includes Low Grade, Anaplastic

4) Pineal Cell Tumours

Lastly, it is important to recognize that regardless of whether a tumour is small, large, fast growing or slow growing, its location is very important – as this determines compaction of adjacent structures and resectability (3).

The nervous system is a complex system for information handling in the body, consisting of billions of neurons and their supporting glial cells. The nervous system is structurally divided into the central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system (PNS), which includes the cranial, spinal, and peripheral nerves (1).

The two cell types that are present in the central and peripheral nervous system, the neurons and glia, have different structure and function. The neuron conducts impulses and is made up of a cell body, axon and dendrites. It may conduct impulses faster if a myelin sheath is present. The glia have short processes and function to support and protect neurons. They participate in neural nutritional and defend cells in the central nervous system. There are 10x more glia than neurons in a mammalian brain, and six different types (1):

When tumours develop in the central nervous system, the signs and symptoms are often related to the area in which they develop. A basic knowledge of the brain lobes is useful in localizing malignancies. Review the table below for further information (2).

Table 1: Cognitive Deficits/Symptoms Based on Brain Mass Location

Epidemiology

The most frequently occurring primary brain tumours are gliomas – a group that includes astrocytomas, oligodendrogliomas (OD) and ependymomas. This group accounts for over 80% of all malignant tumours of the central nervous system, and 40% of all primary brain tumors. Within astrocytomas, the glioblastomas are the most malignant glial tumour and represent 50% of all glial tumours. The incidence is 2 or 3 per 100,000 persons per year (1). Gliomas are rare in adolescents and children, their peak incidence is in the fifth decade, between 50 and 55 years. There is a slight male predominance in all types of CNS tumours except meningiomas.2 The incidence of malignant brain tumours in males is 7.7 per 100,000 person-years for males and 5.4 per 100,000 person-years for females (1).

Risk Factors

Risk factors for primary CNS tumours have been difficult to identify with the majority of cases presenting no clear etiological factors. Positive correlations have been observed between brain tumour occurrence and exposure to synthetic rubber, vinyl chloride, and petroleum refining. It appears that diagnostic radiation is not strongly associated with the development of gliomas (1), however, therapeutic ionizing radiation such as CT scans or X-rays of the head and neck pose a risk (3). Brain tumours can arise in association with genetic syndromes such as neurofibromatosis type 1, Li-Fraumeni, Tuberous Sclerosis, Neurofibromatosis Type II and Turcot Syndrome.

Risk Factors and Epidemiology Summary

Demographics

• 50 - 55 years of age
• Male > female

Industrial Exposures

• Synthetic rubber
• Vinyl chloride
• Petroleum refining

Hereditary Syndromes

• Neurofibromatosis Type 1 and Type 2
• Tuberous sclerosis
• Li-Fraumeni Syndrome
• Turcot Syndrome

There is no useful screen available to be used on the healthy population. However, note should be taken of the patient’s occupational and family history (1).

There can be several different ways to speak about tumours located in the central nervous system. We first discuss the classification seen within the entire central nervous system, and then discuss Gliomas more specifically.

Classification of Primary CNS tumours can be made according to tissue of origin (1):

Classification can also be based on the location of cancer origin. A primary tumour denotes that the cancer began in the brain, whereas a secondary tumour denotes at the cancer began elsewhere and has metastasized to the brain (2).

Gliomas more specifically can be classified based on a combination of histology and grade. We will take a closer look at the classification of Astrocytomas (2):

• Pilocytic Astrocytoma = Grade I tumour
• Diffuse Astrocytoma = Grade II tumour
• Anaplastic Astrocytoma = Grade III tumour
• Glioblastoma = Grade IV tumour

The grade of a tumour describes its characteristics:

• Grade I tumours – slow growing, usually resectable, good prognosis and may be considered benign
• Grade II tumours – grow slightly faster, may reoccur following resection
• Grade III tumours – fast growing and considered malignant. Invade surrounding tissue and recur following resection
• Grade IV tumours – most malignant, rapidly growing cells. These aggressively invade adjacent tissue (3)
• The Grade I and II tumours, pilocytic and diffuse, can be grouped and called low grade tumours while the grade III and IV tumours are considered high grade. For this reason you may hear glioblastomas referred to as Grade IV Astrocytomas, High Grade Astrocytomas or, their historic name of Glioblastoma Multiforme (GBM) (2).

As previously mentioned, tumour location can be one of the most important factors in regards to clinical presentation of a tumour. Size is also important as the degree of compression of adjacent tissue will present with focal neurological deficits that will generally be of upper motor neuron in type. One may see spasticity, hyerreflexia and upgoing plantar reflexes (1).

The follow are the most common signs and symptoms of gliomas as reported by the Glioma Outcomes Project:

• Headaches – 53-57% occurrence
• Seizures – 56% occurrence in patients with grade III lesions
• Memory loss, motor weakness, visual symptoms, language deficit, cognitive and personality changes – 20% occurrence (2)

One should be aware that patients may also present with seizure and raised intracranial pressure. The raised pressure can be the cause of headache, nausea, vomiting, apathy and even poor concentration, memory impairment and personality change (1).

As headache is a common symptom experienced by patients, we discuss important qualities and characteristics to help evaluate possible headache etiology, mechanisms of headache and diagnostic criteria.

Mechanism of Headache: in brain tumours, likely mechanisms of brain headache are traction on the large blood vessels and dura, or compression of the cranial nerve fibers by the tumour. Other structures that are sensitive to pain include the meningeal arteries, the large venous channel of the brain and dura, and subcutaneous tissue and muscles of the skull. The brain parenchyma itself is insensitive to pain (3).

Diagnostic factors: as headache is a common clinical feature of many illnesses, it becomes very important to recognize the characteristics of headache that are associated with tumours. The following is a list of red flag signs and symptoms for headache with a neoplastic etiology (3).

• New headache onset in an adult, esp. over 50 yrs
• Acute, new, usually severe headaches that changed from previous patterns
• Headache on exertion
• Headache onset at night, or early morning
• Headache with neurological signs
• Precipitation of headache with valsalva (coughing, sneezing or bending over)

The International Headache Society have proposed a set of diagnostic criteria to help diagnose headache attributable directly to neoplasm – once these signs or symptoms are seen, neuroimaging is indicated (3):

1. A headache with at least one of the following characteristics in addition to either requirement 3 or 4: progressive, localized, worse in the morning, aggravated by coughing or bending forward
2. Intracranial neoplasm shown on imaging
3. Headache develops in temporal (and usually spatial) relation to the neoplasm
4. Headache resolves within 7 days after surgical removal or volume-reduction of neoplasm on treatment with glucocorticoids

Signs and Symptoms of CNS Tumor Summary

Generalized

• Headache 
• Seizures
• Nausea, Vomiting 
• Neurocognitive dysfunction 
• Memory loss 
• Personalty Changes 
• Papilledema

Focused

• Motor Weakness
• Sensory Loss
• Aphasia
• Visual-Spatial Dysfunction
• Visual Changes

Mechanisms of Spread

Considering the possible mechanisms of spread is important when considering a presenting symptom.

The main mechanism of spread of CNS tumours is via direct infiltration. Malignant or benign, CNS tumours enlarge by infiltrating and/or compressing adjacent tissue which eventually leads to increased intracranial pressure. The tumour may also compress the ventricular system, leading to impaired drainage of cerebrospinal fluid and thus resulting in hydrocephalus (1). Glioblastomas commonly spread through white matter tracts across the corpus callosum, internal capsule, and optic radiations. The local infiltration will manifest as focal neurological deficits (4).

Lymphatic spread is not seen as cerebral tissue lacks a true lymphatic drainage system. Likewise, distant metastasis are rare but are described in patients with extremely aggressive tumours such as glioblastomas that have invaded the dural venous sinus system and in medulloblastomas (1).

Based on history, physical, imaging, and most importantly biopsy, a diagnosis of glioblastoma can be made. However, a working differential diagnosis will help guide the process:

Differential Diagnosis of Brain Mass

Malignant:

• Primary brain tumor (gliomas, meningiomas, pituitary adenoma, vestibular schannoma, primary central nervous system lymphoma, other)
• Metastatic brain tumor (secondary tumor)

Benign

• Vascular disease
• Cerebral infarct (embolus, thrombosis)
• Infection (abscess, viral infection, progressive multifocal leukoencephalopathy)
• Inflammatory (multiple sclerosis, post infectious encephalomyelitis) (1)

History

• Characterize the presenting complaint, with an attention to the following aspects of a neurological history:
• headaches – duration, frequency, alleviating and aggravating factors, quality, pattern
• Seizures
• Syncopal events, nausea and vomiting
• Cognitive dysfunction – including memory problems/mood or personality changes
• Muscle weakness
• Sensory loss
• Aphasia – a disorder of language function

Past Medical History

• Assess family history for any cancers, genetic syndromes (Li-Fraumeni, Turcot, etc)
• Assess industrial exposures to vinyl chloride, radiation
• Assess current health status
• Assess current medications, allergies (2)

Physical Exam

• Conduct a general physical exam
• Conduct a focused neurological exam:

1) Mental Status

• Have them follow at least one complicated command, taking care not to give them any nonverbal cues.
• Test for orientation to person, place, and time.
• If their responses are appropriate and they are able to relate a detailed and coherent medical history, no further mental status testing is necessary

2) Cranial Nerves

• Test visual fields in one eye, both pupillary responses to light, eye movements in all directions, facial strength, and hearing to finger rub.

3) Motor System

• Test strength in the following muscles bilaterally: deltoids, triceps, wrist extensors, hand interossei, iliopsoas, hamstrings, ankle dorsiflexors.
• Test for pronator drift.
• Test finger tapping, finger-to-nose, and heel-knee-shin performance.
• Test tandem gait and walking on the heels.

4) Reflexes

• Test plantar responses and biceps, triceps, patellar, and ankle reflexes bilaterally.

5) Sensation

• Test light touch sensation in all four distal limbs, including double simultaneous stimulation.
• Test vibration sense at the great toes.
• Assess eyes for papilledema as it is a sign of serious pathology. Papilledema suggests the presence of an intracranial mass lesion, benign intracranial hypertension (pseudotumor cerebri), encephalitis, or meningitis (3).

Imaging

There are a myriad of imaging options available for central nervous system neoplasms: we focus our discussion on the most commonly used, contrast-enhanced MRI and Computed Tomography (CT).

Options:

• Gadolinium-Enhanced MRI – Gold Standard
• Computed Tomography (CT)

Gadolinium-Enhanced MRI

Contrast-enhanced MRI is the diagnostic standard for brain tumor imaging. With enhanced sensitivity, MRI provides detailed physiologic and anatomic information. While contrast-enhanced CT is able to detect high-grade lesions, low-grade lesions may be detectable only on MRI. In addition, contrast-enhanced CT may miss small foci of metastatic disease that are visible on MRI (4).

Imaging of high grade glioblastomas usually reveals:

• A heterogeneously contrast-enhancing lesion
• Irregular borders
• Severe edema
• Necrotic center (necrosis is a distinguishing pathological feature of glioblastomas) (4)
• Hypointense on T1-weighted images
• Mass effect (5)

Note that the reason for enhancement between tumours may be different: circumscribed astrocytomas enhance because their blood vessels undergo "chronic glomeruloid degenerative hyalinization" whereas the enhancement in anaplastic astrocytomas and glioblastomas is due to endothelial proliferation (6).

It is also important to recognize that while brain tumor imaging can be helpful in narrowing the differential diagnosis, confirmation of the diagnosis via pathology is necessary in nearly all cases (4).

Computed Tomography

Though use of CT has been replaced by cranial MRI, it still offers many advantages. Namely, CT is very useful in an emergency situation where time constraints are present, or if the patient has contraindication to conventional MRI, either due to claustrophobia or an iron-containing implant. CT may also be advantageous in situations requiring detection of bone or vascular involvement, distant metastases to skull base, or metastases to foramen magnum (5).

Biopsy

A tissue diagnosis is essential in the patient with suspected glioma. Biopsy may be performed via a procedure known as stereotactic biopsy, or at the time of surgical resection of the tumor. Biopsy without surgical resection may be warranted in patients who physically cannot undergo surgery or in patients whose tumors are not amenable to resection.

Stereotactic biopsy is a biopsy procedure that uses CT or MRI imaging and framing devices to allow for accurate tissue localization – frameless stereotactic devices that create a computerized link between the tissue in question and patient surface landmarks have been observed to have an accuracy of 1mm within the intracranial space. Overall, stereotactic image-guided biopsy is a safe diagnostic procedure in a report of 125 stereotactic biopsies, a definitive diagnoses was obtained in 98% of cases (7).

The distinction between the various grades of infiltrating astrocytic neoplasms is based upon four histologic features: nuclear pleomorphism (or nuclear atypia), mitotic figures, endothelial proliferation and necrosis. Glioblastomas, by definition, contain at least three of these four histologic features. The picture below shows necrosis marked by the star. As is characteristic of glioblastomas, the tumour has neoplastic cells at the edge of the necrosis (marked by an arrow in the image below).

As was presented earlier, there are many pathological classifications currently in use. The most predominate is presented here, with an addition of pathological features seen in each class.

No universal staging system is currently in place, however prognostic factors are taken into account to complete the clinical picture. See section on Prognosis for more information.

Malignant gliomas are aggressive and as such are best managed with maximal surgical resection, adjuvant chemotherapy and adjuvant post-operative radiation therapy. We discuss each here.

Surgical Resection

For patients with primary glial tumors, maximum surgical resection is usually recommended, with two exceptions: Low grade gliomas, for which the impact of maximal resection is still unknown, and diffuse pontine gliomas. Maximal section refers to removal of visibly abnormal tissue as seen either via T1 weighted MRI or intraoperatively and is completed to a degree that is consistent with maximal functional preservation of neurologic tissue. Maximal resection provides certain benefits:

• Maximal resection provides a larger tissue sample for detailed analysis, which increases the likelihood of accurate diagnosis and thus can help direct therapy
• Maximal resection rapidly alleviated symptoms
• Maximal resection facilitates the tapering and discontinuation of corticosteroid use, a drug class associated with multiple side effects
• Maximal resection may improve response to any postoperative radiation or adjuvant therapies

While maximal resection is considered the most preferable, the tumor location and size factors heavily into surgical feasibility.

Radiation Therapy

Adjuvant radiation therapy (RT) directed at any residual disease improves survival after surgical resection. A main objective in this type of therapy is to minimize radiation to normal brain tissue and for this reason Whole Brain Radiation Therapy (WBRT) has been replaced with Focal External Beam RT, called Involved Field RT (IFRT). Today there are many RT techniques available, including 3D conformational RT, Intensity-Modulated RT, Reirradiation, Stereotactic radiosurgery and interstitial brachytherapy.

Adjuvant chemotherapy

Use of temozolomide, an oral alkylating agent, is the current standard for adjuvant chemotherapy.  The combination of temozolomide plus radiation therapy shows a statistically significant prolongation of patient survival and was particularly effected in patients under 50 years of age.

The major predictive factor for benefit from chemotherapy is if the patient has MGMT methylation: methylation of the promoter for methyl guanine methyl transferase (MGMT). The enzyme methyl guanine methyl transferase is responsible for DNA repair after chemotherapy with an alkylating agent. As a tumor develops, this gene may be silenced, thus the patient’s DNA does not get repaired, and the effectiveness of chemotherapy is enhanced. The presence of MGMT methylation may also influence rates of clinical relapse, as studies have shown that patients with the methylation had a longer time interval before initial relapse.

As elderly patients constitute approximately one half of those with malignant gliomas and also have a poorer prognosis, debate has opened on best practice within this population. For instance, while RT has shown benefit, the optimal dose and schedule remains unclear with many elderly unable to tolerate the regimen used in younger patients. It has been suggested that lower doses of radiation and shorter course be used as they yielded comparable survival rates and decreased use of post-treatment corticosteroid therapy.

Follow-up

Follow up imaging is often performed as deemed clinically necessary, taking patient factors such as age and prognosis into account.

Major Prognostic Factors for those with CNS Tumours:

• Age
• Tumor Grade
• Karnofsky Performance Status Score*
• Extent of surgical resection
• Molecular alterations: IDH1, IDH2, MGMT, LOH 19q

In addition to these main factors, others important factors for prognosis include use of adjuvant temozolamide, mental status and corticosteroid use at baseline.

KPS, or Karnofsky performance status, is a bounded rating system to assess patient performance – see the table below.

Survival of patients with astrocytomas is variable and is not entirely explained by histologic grading or clinical parameters. It has been found that genetic mutations have prognostic value and as such testing for these changes has become widespread as it directly influences therapeutic decisions.  For instance, LOH 1p (Loss of heterozygosity on chromosome 1p) and LOH 19q are important in predicting response to chemotherapy in oligodendroglial tumors.  As stated previously, another major predictive factor for benefit from chemotherapy is if the patient has MGMT methylation: methylation of the promoter for methyl guanine methyl transferase (MGMT). The MGMT enzyme is responsible for DNA repair after chemotherapy with an alkylating agent. As a tumor develops, this gene may be silenced, thus the patient’s DNA does not get repaired, and the effectiveness of chemotherapy is enhanced. The presence of MGMT methylation may also influence rates of clinical relapse, as studies have shown that patients with the methylation had a longer time interval before relapse.

Karnofsky Performance Status Scale: An abbreviated table is presented above.

1) Review the anatomy of the central nervous system

2) Describe what signs and symptoms arise from brain lesions based on location

3) State the incidence of gliomas, and glioblastomas

Within astrocytomas, the glioblastomas are the most malignant glial tumour and represent 50% of all glial tumours. The incidence is 2 or 3 per 100,000 persons per year

4) State the risk factors for brain tumors

Demographics

• 50 - 55 years of age
• Male > female

Industrial Exposures

• Synthetic rubber
• Vinyl chloride
• Petroleum refining

Hereditary Syndromes

• Neurofibromatosis Type 1 and Type 2
• Tuberous sclerosis
• Li-Fraumeni Syndrome
• Turcot Syndrome

5) State the recommended screening procedure for brain tumor

There is no useful screen available to be used on the healthy population. However, note should be taken of the patient’s occupational and family history.

6) State the routes of spread of CNS tumours

• Local infiltration (white matter tracts)
• No lymphatic spread
• Rare distant metastases

7) Understand the classification of CNS tumors

Gliomas more specifically can be classified based on a combination of histology and grade. We will take a closer look at the classification of Astrocytomas:

• Pilocytic Astrocytoma = Grade I Tumour
• Diffuse Astrocytoma = Grade II tumour
• Anaplastic Astrocytoma = Grade III Tumours
• Glioblastoma = Grade IV tumour

8) Describe the signs and symptoms of CNS tumours with emphasis on headache

Signs and symptoms are usually: headache, seizures, memory loss, personality change, motor weakness, visual symptoms, language deficits.

Generalized

• Headache 
• Seizures
• Nausea, Vomiting 
• Neurocognitive dysfunction 
• Memory loss 
• Personalty Changes 
• Papilledema

Focused

• Motor Weakness
• Sensory Loss
• Aphasia
• Visual-Spatial Dysfunction
• Visual Changes

9) Name the red flag signs of headache of possible neoplastic etiology

• New headache onset in an adult, esp. over 50 yrs
• Acute, new, usually severe headaches that changed from previous patterns
• Headache on exertion
• Headache onset at night, or early morning
• Headache with neurological signs
• Precipitation of headache with valsalva (coughing, sneezing or bending over)

10) List the differential diagnosis of a brain mass

To generate ideas, split categories into the possible malignant vs. benign etiologies.

11) Describe an appropriate history and physical to be performed on a patient with suspected brain mass

• Characterize the presenting complaint, assess neurological functioning, assess past medical history, family history, risk factor exposure, current medications and allergies
• Complete a general physical and a detailed neurological exam, keeping danger signs in mind

12) Outline imaging techniques used in CNS tumours

• MRI (if available), but CT usually sufficient

13) Outline characteristic features seen on imaging of a high grade glioma

Imaging of high grade glioblastomas usually reveals:

• Heterogeneous contrast-enhancing lesion
• Irregular borders
• Severe edema
• Frequently, a necrotic center (necrosis is a distinguishing pathological feature of glioblastomas)
• Hypointense on T1-weighted images
• Mass effect

14) Describe standard treatment protocol for high grade gliomas

Malignant gliomas are aggressive and as such are best managed with maximal surgical resection, adjuvant chemotherapy and adjuvant post-operative radiation therapy.

15) Describe biopsy techniques employed today and importance of biopsy in diagnosis

Biopsy is either stereotactic or done at time of surgical resections. Tissue pathology is requires for diagnosis. Stereotactic biopsy is a biopsy procedure that uses CT or MRI imaging and framing devices to allow for accurate tissue localization.

16) Describe the prognostic factors for brain tumours with emphasis on molecular implications

• Age
• Tumor Grade
• Karnofsky Performance Status Score*
• Extent of surgical resection
• Molecular alterations: IDH1, IDH2, MGMT, LOH 19q

17) Describe how treatment regimens may change for elderly patients

It has been suggested that lower doses of radiation and shorter course be used as they yielded comparable survival rates and decreased use of post-treatment corticosteroid therapy.

18) Describe the characteristic pathology of a high grade glioma

19) Describe what the recommended follow up protocol is after receiving treatment for a high grade astrocytoma

Follow up imaging is often performed as deemed clinically necessary, taking patient factors such as age and prognosis into account

20) What staging system is used for Central Nervous System tumours?

No widespread staging system is currently in use.

Introduction

1) Wong ET, WU KW. Clinical presentation and diagnosis of brain tumors. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

2) Murphy GP, Lawrence WM, Lenhard RE. American Cancer Society Textbook of Clinical Oncology. 2nd ed. American Cancer Society: Atlanta; 1995

3) Louis DN, Schiff D, Batchelor T. Classification of gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

Anatomy Review

1) Mescher AL. Junquiera’s Basic Histology: Text & Atlas. 12th ed. United States of America: The McGraw Hill Companies ;2012.

2) Southwick, FS. Pathogenesis, clinical manifestations and diagnosis of brain abscess. In:UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

3) Morton D.A., Foreman K.B., Albertine K.H. (2011). Chapter 16. Brain. In D.A. Morton, K.B. Foreman, K.H. Albertine (Eds), The Big Picture: Gross Anatomy. Retrieved August 14, 2013 from http://www.accessmedicine.com/content.aspx?aID=8666950.

Epidemiology

1) Shonka NA, Hsu SH, Yung WA, Mahajan A, Prabhu S. Chapter 37. Tumors of the Central Nervous System. In: Kantarjian HM, Wolff RA, Koller CA, eds.The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8312079. Accessed July 10, 2013.

2) Neal; AJ, Hoskin, PJ. Clinical Oncology: Basic Principles and Practice. 3rd ed. New York: Oxford University Press; 2003.

3) The NeuroOncology Tumour Group. BC Cancer Agency [Internet]. Place of publication: publisher. [updated June 2011: cited July 10 2013] Available from: http://www.bccancer.bc.ca/health-info/types-of-cancer/brain-central-nervous-system/brain-central-nervous-system/

4) Neal; AJ, Hoskin, PJ. Clinical Oncology: Basic Principles and Practice. 3rd ed. New York: Oxford University Press; 2003.

Screening

1) The NeuroOncology Tumour Group. BC Cancer Agency [Internet]. Place of publication: publisher. [updated June 2011: cited July 10 2013] Available from: http://www.bccancer.bc.ca/PPI/TypesofCancer/BrainnCentralNervousSystem/default.htm

Classification

1) Neal; AJ, Hoskin, PJ. Clinical Oncology: Basic Principles and Practice. 3rd ed. New York: Oxford University Press; 2003.

2) Louis DN, Schiff D, Batchelor T. Classification of gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

3) The NeuroOncology Tumour Group. BC Cancer Agency [Internet]. Place of publication: publisher. [updated June 2011: cited July 10 2013] Available from: http://www.bccancer.bc.ca/PPI/TypesofCancer/BrainnCentralNervousSystem/default.htm

Signs & Symptoms

1) Neal; AJ, Hoskin, PJ. Clinical Oncology: Basic Principles and Practice. 3rd ed. New York: Oxford University Press; 2003.

2) Batchelor T, Curry WT. Clinical manifestations and initial surgical approach to patients with malignant gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

3) Lay CL, Sun-Edelstein C. Brain tumour headache. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

4) MD Anderson: Shonka NA, Hsu SH, Yung WA, Mahajan A, , Prabhu S. Chapter 37. Tumors of the Central Nervous System. In: Kantarjian HM, Wolff RA, Koller CA, eds.The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8312079. Accessed July 10, 2013.

5) Wen Y, Loeffler JS. Overview of the clinical manifestation, diagnosis and management of patients with brain metastases. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

Diagnosis

1) Southwick FS. Pathogenesis, clinical manifestations and diagnosis of brain abscess. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

2) Wong ET, Wu JK. Clinical presentation and diagnosis of brain tumors. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

3) Douglas G. The detailed neurologic examination in adults. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

4) Shonka NA, Hsu SH, Yung WA, Mahajan A, , Prabhu S. Chapter 37. Tumors of the Central Nervous System. In: Kantarjian HM, Wolff RA, Koller CA, eds.The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8312079. Accessed July 10, 2013.

5) Wong ET, Wu JK. Clinical presentation and diagnosis of brain tumors. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

6) Recht D. Diagnosis and classification of low grade gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

7) Batchelor T, Curry WT. Clinical manifestations and initial surgical approach to patients with malignant gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

Pathology

1) Batchelor T, Louis, DN. Pathogenesis and biology of malignant tumors. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

2) Neoplasms and Paraneoplastic Disorders. In: Ropper AH, Samuels MA, eds. Adams and Victor’s Principles of Neurology. 9th ed. New York: McGraw-Hill; 2009. http://www.accessmedicine.com/content.aspx?aID=3637579. Accessed July 9, 2013.

3) Shonka NA, Hsu SH, Yung WA, Mahajan A, Prabhu S. Chapter 37. Tumors of the Central Nervous System. In: Kantarjian HM, Wolff RA, Koller CA, eds.The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8312079. Accessed July 10, 2013.

Management

1) Batchelor T, Curry WT. Clinical manifestations and initial surgical approach to patients with malignant gliomas. In:UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

2) Batchelor T. Adjuvant chemotherapy for malignant gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

Prognosis

1) Batchelor T, Curry WT. Clinical manifestations and initial surgical approach to patients with malignant gliomas. In:UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.

2) Batchelor T, Louis DN. Pathogenesis and biology of malignant gliomas. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, Ma, 2013.