Introduction

Neuro-oncology is a broad and rapidly evolving field that comprises portions of neurology, neurosurgery, pediatrics, medical oncology, radiation oncology, neuroradiology, neuropathology, cancer rehabilitation, and palliative care. Neuro-oncology covers the diagnosis and management of primary and metastatic tumors of the central nervous system (CNS) and complications of systemic cancers or cancer treatments. The goal of this 2-part special report is to provide an overview of the epidemiology, presentation, diagnostic evaluation, and management for most common CNS tumors. The first part of the series focuses on the epidemiology, presentation, and diagnostic evaluation.

Epidemiology

Brain tumors account for only about 1.4% of all cancers,1 and malignant CNS tumors in people more than age 40 have an average annual age-adjusted mortality rate of 9.01 per 100,000, making brain tumors the 29th most common cause of death overall and 14th among cancer deaths. The most frequently reported histologies from the Central Brain Tumor Registry of the United States (CBTRUS) are meningioma (37.1%), pituitary tumors (16.5%), and glioblastoma (14.7%). The most common malignant CNS tumor is glioblastoma (47.7%), which accounts for the majority of gliomas (56.6%). Estimates suggest 26,170 malignant and 60,800 nonmalignant brain tumors will be diagnosed in the US in 2019 with a slightly higher incidence among women (25.32/100,000) compared to men (20.59/100,000 for men).1

From 2011 to 2015, the average annual mortality rate in the US was 4.37 per 100,000 deaths with 77,375 attributed to primary CNS tumors. It is estimated that 16,830 deaths will be attributed to primary malignant CNS tumors in the US in 2018 with approximately 12,000 deaths from glioblastoma. The overall inclusive 5-year relative survival for a primary malignant CNS tumor (including lymphomas and leukemias, pituitary and pineal gland tumors, and olfactory tumors of the nasal cavity) is 35.0%. This overall survival is correlated indirectly with age (decreased survival with increasing age). The 5-year survival rate for those age 0 to 19 years is 74.1%, age 20 to 44 years is 62.2%, 45 to 54 years is 33.5%, 55 to 64 years is 18.5%, 65 to 74 years is 11.5%, and more than 75 years is 6.1%. Survival after diagnosis with a nonmalignant CNS tumor also varies with an overall 5-year relative survival after diagnosis of 91%.1

Risk Factors

Ionizing radiation is the only established environmental risk factor for developing brain tumors. Moderate to high-dose ionizing radiation exposure is associated with glioma and meningioma.2 The exposure appears to have a greater effect with younger age.3,4

Genetic Risk Factors. There are multiple genetic tumor syndromes such as Li-Fraumeni, neurofibromatosis (type 1 and 2), tuberous sclerosis, Gorlin’s syndrome, Turcot’s syndrome and von Hippel-Lindau (Table 1).5

Clinical Evaluation

Presenting Symptoms

Diagnosis of CNS neoplasms begins with a thorough history and physical examination. Presenting symptoms can be nonspecific and/or focal. Typically, tumor symptoms have subacute onset, in contrast to vascular disorders, which typically have acute onset, or degenerative disorders, which typically have chronic onset. Benign or low-grade neoplasms usually have a slower symptom onset than malignant tumors. Review of systems often reveals fatigue, weight loss, lethargy, and night sweats common among many cancers.6

Seizures. A common symptom, seizures occur with approximately 30% of brain tumors and often begin focally then secondarily generalize. If the semiology of the focal portion is specific, then localization is possible or the postictal phase results in a Todd’s paralysis or aphasia. Low-grade gliomas have a higher incidence of seizures (60%-75%) compared with high-grade gliomas (25%-60%), meningiomas (20%-50%), and metastases (20%-35%).7

Headache. More than 50% of individuals with a brain tumor have headache as a presenting symptom, but it is rarely the only symptom present. Nausea and vomiting can be associated with headaches and are particularly suggestive of a brain tumor when they occur in the morning with rising, reflecting increased intracranial pressure. The character of headache does not reliably distinguish a brain tumor diagnosis; however, people who have headaches that wake them up at night or occur in the early morning should be evaluated more urgently.8,9

Dizziness. More frequently a vague complaint or sense of vertigo suggesting a cerebellopontine angle or cerebellum tumor (typically associated with ipsilateral dysmetria or ataxia), dizziness is also a frequent presenting symptom.10

Physical Examination

If focal signs are present on physical examination, then specific localization is often possible by discerning the pattern (Table 2). Supratentorial lesions result in contralateral long tract signs with cortical findings (eg, aphasia, acalculia, or visual impairment). Language involvement suggests a dominant hemisphere lesion. Brain stem tumors are localized with ipsilateral cranial nerve findings with associated contralateral long tract findings.

Radiographic Examination

General symptoms including headache associated with nausea and vomiting, particularly in the early morning are suggestive of an intracranial mass lesion. Lethargy, somnolence, and papilledema associated with these symptoms indicates a patient in urgent need of imaging.8

CT. The most common initial radiographic evaluation for suspected brain tumors is CT, despite the need for subsequent MRI because CT is useful for identifying acute hematoma, mass effect, herniation, and hydrocephalus. Additionally, CT can identify tumor calcifications to suggest either, craniopharyngioma (suprasellar), oligodendroglioma (intra-axial) or meningioma (extra-axial) (Figure 1A).11

Figure 1. Images from a woman, age 58, who presented after 2 weeks of progressively worsening lethargy then somnolence in the context of odd behavior for the previous 3 months. Initial noncontrast head CT shows an isodense lesion in the left frontal region with surrounding edema, mass effect, and effacement of the lateral ventricle (A). T1 imaging (B, C) and T1 postcontrast sagittal image (D) show an extra-axial mass with homogenous contrast enhancement.

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Figure 1. Images from a woman, age 58, who presented after 2 weeks of progressively worsening lethargy then somnolence in the context of odd behavior for the previous 3 months. Initial noncontrast head CT shows an isodense lesion in the left frontal region with surrounding edema, mass effect, and effacement of the lateral ventricle (A). T1 imaging (B, C) and T1 postcontrast sagittal image (D) show an extra-axial mass with homogenous contrast enhancement.

MRI. Anatomic imaging sequences for brain tumor diagnosis include T1, T2, fluid attenuation inversion recovery (FLAIR) and postcontrast T1. Volumetric protocols can be performed for high-resolution evaluation or treatment planning (eg, radiation treatment planning or surgical navigation). A T2* gradient echo or susceptibility weighted imaging (SWI) sequence is sensitive for blood products or calcifications. These sequences help define anatomic location (eg, frontal or occipital) and space (eg, intra-axial, extra-axial, intraventricular, intraosseous, or scalp). Using these anatomic sequences with patterns of disease, history, and physical examination findings typically establishes a working differential diagnoses.

Figure 2: Images from a man, age 44, who presented with a new onset seizure. His MRI findings reveal a left anterior temporal mass (A), and T1 imaging shows a hypointense mass (B,C); whereas, T2/FLAIR is hyperintense without significant contrast enhancement (D), and DWI and ADC demonstrate increased diffusion within the tumor (E, F). Pathology after surgical resection was consistent with an astrocytoma WHO grade 2, IDH wild type and ATRX mutant. Abbreviations: ADC, apparent diffusion coefficient ; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; WHO, World Health Organization.

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Figure 2: Images from a man, age 44, who presented with a new onset seizure. His MRI findings reveal a left anterior temporal mass (A), and T1 imaging shows a hypointense mass (B,C); whereas, T2/FLAIR is hyperintense without significant contrast enhancement (D), and DWI and ADC demonstrate increased diffusion within the tumor (E, F). Pathology after surgical resection was consistent with an astrocytoma WHO grade 2, IDH wild type and ATRX mutant. Abbreviations: ADC, apparent diffusion coefficient ; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; WHO, World Health Organization.

A homogenously enhancing extra-axial mass suggests meningioma, but the differential diagnosis includes hemangiopericytoma, dural-based metastasis, and lymphoma (Figure 1). A solitaryT2/FLAIR hyperintense intra-axial lesion that does not enhance with contrast suggests low-grade glioma (Figure 2). A solitary heterogeneously enhancing intra-axial lesion suggests high-grade glioma or solitary metastasis (Figure 3). Multiple heterogeneously enhancing intra-axial lesions suggests a metastatic disease or abscesses (Figure 4).

Figure 3:  Images from a woman, age 58, after 3 weeks of progressive right-sided weakness. The MRI reveals an intra-axial T1 isointense (A), T2 heterogenous (B) heterogeneously enhancing mass of the cuneus with surround T2/FLAIR edema surrounding the lesion (C,D). Pathology from surgical resection was consistent with glioblastoma World Health Organization (WHO) grade 4, IDH wild type.

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Figure 3: Images from a woman, age 58, after 3 weeks of progressive right-sided weakness. The MRI reveals an intra-axial T1 isointense (A), T2 heterogenous (B) heterogeneously enhancing mass of the cuneus with surround T2/FLAIR edema surrounding the lesion (C,D). Pathology from surgical resection was consistent with glioblastoma World Health Organization (WHO) grade 4, IDH wild type.

Figure 4: Images from a man, age 74, who had a history of metastatic melanoma. The imaging studies reveal 2 new heterogeneously enhancing brain lesions in the left frontal (A) and temporal lobes (B). These lesions were at the gray-white junction consistent with oligometastatic spread to the brain. Stereotactic radiosurgery of both lesions was performed with the goal of providing local tumor control on both sides.

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Figure 4: Images from a man, age 74, who had a history of metastatic melanoma. The imaging studies reveal 2 new heterogeneously enhancing brain lesions in the left frontal (A) and temporal lobes (B). These lesions were at the gray-white junction consistent with oligometastatic spread to the brain. Stereotactic radiosurgery of both lesions was performed with the goal of providing local tumor control on both sides.

Diffusion-Weighted Imaging. Measuring the relative movement of water through tissue, diffusion-weighted imaging (DWI) has become a standard sequence that can be critical for the diagnosis of stroke, which can occur around the time of surgery and result in findings consistent with early psuedo-progression. Of particular use in distinguishing tumors (no restriction) from abscess (restriction), DWI is used to create apparent diffusion coefficient (ADC) maps associated with highly cellular processes (eg, lymphoma, medulloblastoma, and glioblastoma.)11,12 Additionally, ADC minimum values can help distinguish tumefactive demyelinating lesions from primary CNS lymphomas and gliomas.13

Diffusion Tensor Imaging. An application of diffusion-weighted imaging over 3 dimensions, diffusion tensor imaging (DTI) measures both diffusivity and direction and is used clinically for DTI-tractography to isolate a fiber tract of interest (eg, corticospinal tract or arcuate fasciculus). Once the tract is isolated, it can be overlaid on a volumetric study for presurgical planning and neuronavigation.11,12

Functional MRI. Using changes in local blood oxygen level-dependent (BOLD) signal, functional MRI (fMRI) indirectly assesses neuronal activity, and task-based fMRI can be used to identify eloquent cortical structures including motor and speech functions for preoperative planning.14 Resting state fMRI has also been used to identify eloquent structures, although there is less experience with this technique compared with task-based fMRI.15

Perfusion MRI. Focused on assessing the degree of tumor angiogenesis and capillary permeability, perfusion imaging shows whether there is increased tumor vascularity, which is associated with increased grade, particularly with glial tumors (notable exceptions are extra-axial tumors such as meningioma). Perfusion changes can help guide diagnostic biopsy procedures and identify early progression of tumors (Figure 5).

Figure 5: A man, age 43, who presented with headache and early morning nausea and vomiting had MRI that revealed an intra-axial mass in the left occipital lobe with heterogeneous contrast enhancement. MR perfusion showed increased cerebral blood flow heterogeneously throughout the tumor. Pathology demonstrated glioblastoma World Health Organization (WHO) grade 4.

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Figure 5: A man, age 43, who presented with headache and early morning nausea and vomiting had MRI that revealed an intra-axial mass in the left occipital lobe with heterogeneous contrast enhancement. MR perfusion showed increased cerebral blood flow heterogeneously throughout the tumor. Pathology demonstrated glioblastoma World Health Organization (WHO) grade 4.

MR Spectroscopy. Used to measure the metabolic profile of a segment of tissue, MR spectroscopy measures specific metabolites of interest for brain tumors including N-acetylaspartate (NAA), a marker of neuronal integrity; creatine (Cr), a marker of cellular metabolism used as an internal reference; choline (Cho), a marker of cell-membrane turnover; and lipid-lactate (Lac) (Figure 6).11,12

Figure 6: A man, age 38, had a grade 3 oligodendroglioma treated with radiation. Follow up images shown here reveal progression of tumor (T2/FLAIR signal). MR spectroscopy demonstrated contralateral normal spectrum and Hunter’s angle (A), ipsilateral areas suspicious for tumor with reversal of Hunter’s angle (B), and radiation necrosis (C).

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Figure 6: A man, age 38, had a grade 3 oligodendroglioma treated with radiation. Follow up images shown here reveal progression of tumor (T2/FLAIR signal). MR spectroscopy demonstrated contralateral normal spectrum and Hunter’s angle (A), ipsilateral areas suspicious for tumor with reversal of Hunter’s angle (B), and radiation necrosis (C).

Positron Emission Tomography. A nuclear medicine tracer study, positron emission tomography (PET) can track any of several tracers, but the most commonly used is 18 flourodeoxyglucose (FDG), a metabolic tracer that activates in metabolically active cancers, infections, or inflammation of the brain. Because of the high uptake of this tracer in the brain, FDG-PET has found limited utility in the brain compared with its widespread use for other solid organ cancers (Figure 7).11,12

Figure 7: A woman, age 39, who had metastatic breast cancer to the brain that was treated with stereotactic radiosurgery had follow up imaging of the tumor treatment area revealing a continued increased enhancement concerning for tumor progression or radiation necrosis (A). The fluorodeoxyglucose-positron emission tomography (FDG-PET) image of her lesion shows moderate tracer uptake consistent with active tumor at the site (B). Pathology demonstrated a preponderance of active tumor.

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Figure 7: A woman, age 39, who had metastatic breast cancer to the brain that was treated with stereotactic radiosurgery had follow up imaging of the tumor treatment area revealing a continued increased enhancement concerning for tumor progression or radiation necrosis (A). The fluorodeoxyglucose-positron emission tomography (FDG-PET) image of her lesion shows moderate tracer uptake consistent with active tumor at the site (B). Pathology demonstrated a preponderance of active tumor.

Digital Subtraction Angiography. A common and widespread diagnostic and potentially therapeutic modality, digital subtraction angiography (DSA) can often show the significant tumor-feeding vessels, which aids in surgical planning. Preoperative embolization can limit blood loss, particularly for dural-based or extradural tumors (eg, meningioma, Figure 8).16

Figure 8. Digital Subtraction Angiography. A lateral left internal carotid injection from the same case shown in Figure 1 reveals an anteriorly based tumor blush indicating a hypervascular lesion. Arrow demonstrates tumor blush consistent with meningioma (A). Lateral superselective left anterior cerebral artery branch catheterization shows an artery feeding the tumor. Arrow demonstrates feeding arterial pedicle (B). Lateral superselective left anterior cerebral artery branch catheterization demonstrating embolization of the feeding pedicle with absence of tumor blush. Arrow demonstrates intra-arterial embolization material (C).

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Figure 8. Digital Subtraction Angiography. A lateral left internal carotid injection from the same case shown in Figure 1 reveals an anteriorly based tumor blush indicating a hypervascular lesion. Arrow demonstrates tumor blush consistent with meningioma (A). Lateral superselective left anterior cerebral artery branch catheterization shows an artery feeding the tumor. Arrow demonstrates feeding arterial pedicle (B). Lateral superselective left anterior cerebral artery branch catheterization demonstrating embolization of the feeding pedicle with absence of tumor blush. Arrow demonstrates intra-arterial embolization material (C).

Summary. See Table 3 for a summary of common uses of various imaging modalities. See Table 4 for comparison of common brain pathologies and diagnostic differences.

Biomarkers

Blood and cerebrpspinal fluid (CSF) biomarkers and liquid biopsy for high grade gliomas are in preliminary stages of testing including cell-free DNA techniques.17,18 Extracellular vesicles in blood samples are also an area of active investigation.19

Pathology

A tissue sample derived from biopsy remains the highest standard and is fundamental for establishing diagnosis. A full review of pathology findings is beyond the scope of this article; however, several publications are dedicated to recent updates in this area.20

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3. Taylor AJ, Little MP, Winter DL, et al. Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol. 2010;28(36):5287-5293.

4. Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006;98(21):1528-1537.

5. Vijapura C, Saad Aldin E, Capizzano AA, et al. Genetic syndromes associated with central nervous system tumors. Radiographics. 2017;37(1):258-280.

6. Armstrong TS, Vera-Bolanos E, Acquaye AA, et al. The symptom burden of primary brain tumors: evidence for a core set of tumor- and treatment-related symptoms. Neuro Oncol. 2016;18(2):252-260.

7. Englot DJ, Chang EF, Vecht CJ. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134:267-285.

8. Larner AJ. Not all morning headaches are due to brain tumours. Pract Neurol. 2009;9(2):80-84.

9. Goffaux P, Fortin D. Brain tumor headaches: from bedside to bench. Neurosurgery. 2010;67(2):459-466.

10. Comelli I, Lippi G, Campana V, Servadei F, Cervellin G. Clinical presentation and epidemiology of brain tumors firstly diagnosed in adults in the emergency department: a 10-year, single center retrospective study. Ann Transl Med. 2017;5(13):269.

11. Mabray MC, Barajas RF, Cha S. Modern brain tumor imaging. Brain Tumor Res Treat. 2015;3(1):8-23.

12. Villanueva-Meyer JE, Mabray MC, Cha S. Current clinical brain tumor imaging. Neurosurgery. 2017;81(3):397-415.

13. Mabray MC, Cohen BA, Villanueva-Meyer JE, et al. Performance of apparent diffusion coefficient values and conventional MRI features in differentiating tumefactive demyelinating lesions from primary brain neoplasms. AJR Am J Roentgenol. 2015;205(5):1075-1085.

14. Håberg A, Kvistad KA, Unsgård G, Haraldseth O. Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome. Neurosurgery. 2004;54(4):902-914; discussion 14-15.

15. Shimony JS, Zhang D, Johnston JM, et al. Resting-state spontaneous fluctuations in brain activity: a new paradigm for presurgical planning using fMRI. Acad Radiol. 2009;16(5):578-583.

16. Raper DM, Starke RM, Henderson F Jr, et al. Preoperative embolization of intracranial meningiomas: efficacy, technical considerations, and complications. AJNR Am J Neuroradiol. 2014;35(9):1798-1804.

17. Ahmed KI, Govardhan HB, Roy M, et al. Cell-free circulating tumor DNA in patients with high-grade glioma as diagnostic biomarker - a guide to future directive. Indian J Cancer. 2019;56(1):65-69.

18. Westphal M, Lamszus K. Circulating biomarkers for gliomas. Nat Rev Neurol. 2015;11(10):556-566.

19. Hallal S, Ebrahimkhani S, Shivalingam B, et al. The emerging clinical potential of circulating extracellular vesicles for non-invasive glioma diagnosis and disease monitoring. Brain Tumor Pathol. 2019;36(2):29-39.

20. Bienkowski M, Furtner J, Hainfellner J. Clinical neuropathology of brain tumors. Handb Clin Neurology. 2017;145(477-534..

BJW is a consultant for Monteris Medical