Head: Intracranial – gliomas, and meningiomas and extracranial – orbits, internal auditory canals, and skull base

Primary brain tumor classification

Central nervous system tumors are currently classified based on histologic features and the particular tumor cells of origin. Examination of histologic features includes assessing the general degree of tumor cellularity (i.e., cell density), architecture of the tumor, organization of cellular arrangements (e.g., rosette formations, whirling patterns, angiogenesis), cytologic features of the tumor cells themselves (e.g., identification of cellular processes, cytoplasm characteristics), and cytologic atypia suggestive of malignancy. The use of specialized histochemical or immunohistochemical stains, including glial fibrillary acidic protein (GFAP), further help differentiate the particular type of brain tumor. Table 23-1 summarizes the main classifications of primary intracranial central nervous system tumors.

Neuroimaging in brain tumors

Modern neuroimaging techniques and biomarkers in brain tumors are intimately tied to clinical understanding of in vivo human brain tumor behavior. Almost all brain tumor treatment decisions are based on neuroimaging findings and interpretations ( Figure 23-1 ).

Magnetic resonance imaging (MRI) constitutes the most widely used modality for both structural and physiologic imaging, followed by computed tomography (CT) and molecular imaging techniques such as positron emission tomography (PET). In fact, the first medical use of MRI was in describing the characteristics of a patient with a primary brain tumor. Novel contrast agents, MR pulse sequences, and molecular tracers, combined with postprocessing techniques using advanced quantification, simulation, and computer vision algorithms can provide the clinician with a host of information on which to base treatment decisions.

Standard MRI. The minimal MR examination of a patient with a primary brain tumor consists of a T2-weighted, fluid-attenuated inversion recovery (FLAIR), and both a pre- and postcontrast T1-weighted image series. Gadolinium contrast agents are the most widely used in MR brain examinations because of hyperintense (bright) contrast on T1-weighted images due to the significant increase in longitudinal relaxivity (an MR property), which accounts for the increased signal seen.

Diffusion MRI. Diffusion MRI is a physiologic imaging technique that can be used to quantify the apparent diffusion coefficient (ADC), a quantity representing the magnitude of microscopic motion of water molecules. ADC is inversely proportional to cell density, likely reflecting the degree of extracellular space, but ADC also is sensitive to edema and necrosis. Thus, ADC is potentially clinically useful for assessing both cytotoxic and antiangiogenic treatment response. ^, Diffusion tensor MRI is a modification of the standard diffusion MR pulse sequence where direction as well as magnitude is quantified. Diffusion of water molecules is anisotropic in the central nervous system, meaning water molecules diffuse faster in one particular direction compared with other directions. Myelination and cylindrical symmetry in cerebral white matter regions creates high diffusion anisotropy in the normal brain. This anisotropy can be exploited to create pseudo-axonal tracts for visualization and quantification of white matter integrity and connectivity, a technique termed diffusion tensor tractography . Registration of ADC maps obtained from patients over time allow for voxelwise changes in ADC to be quantified, a technique termed functional diffusion mapping (fDM ). ^{, ,} FDMs allow for the visual assessment and quantification of tumor response to treatment, and are particularly useful when tumors are highly heterogeneous.

Perfusion MRI. Perfusion MRI techniques are useful for detection and quantification of neovascularization, which is characteristic of malignant transformation in brain tumors. Perfusion MRI can be performed using the susceptibility (T2*) contrast changes observed during injection of an exogenous (typically gadolinium-based) contrast agent in a first-pass bolus tracking experiment termed dynamic susceptibility contrast (DSC)-MRI . DSC-MRI is a quick (typically less than 2 minutes) scan that can be used to easily estimate relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time (MTT) and allows for quantification of vessel permeability using a global leakage correction algorithm (K2). Perfusion MRI can also be performed using assessment of longer-lasting longitudinal relaxivity changes caused by injection of exogenous MR contrast agents. By obtaining dynamic T1-weighted images over 8–10 minutes and applying a simple two-compartment pharmacokinetic model to the resulting signal-vs-time curves, dynamic contrast enhanced (DCE)-MRI estimates of blood volume fraction ( v _e ) and vascular permeability ( K ^trans ) can be obtained. Arterial spin labeling (ASL) is a perfusion MRI technique that magnetically tags arterial blood water and images the resulting water once it enters the cerebral vasculature, effectively using blood water as an endogenous contrast agent. Absolute quantification of cerebral blood flow (CBF) can be obtained using ASL techniques.

Functional MRI. Functional MRI (fMRI), or more specifically blood oxygenation level dependent (BOLD) fMRI, is commonly used during surgical planning in gliomas to avoid important functional regions of the brain. During a functional paradigm such as finger tapping, auditory cues, visual stimuli, or language-specific tasks, regions of the cortex responsible for these tasks consume a higher level of oxygen, resulting in different concentrations of oxyhemoglobin and deoxyhemoglobin within these regions. The difference in magnetic susceptibility between oxyhemoglobin (diamagnetic) and deoxyhemoglobin (paramagnetic) causes signal differences when scanned using MRI, which can be used to create maps of functional activation.

NMR Spectroscopy. Single-voxel nuclear magnetic resonance spectroscopy (MRS) or multivoxel chemical shift imaging (CSI) can be used to quantify brain tumor metabolites having NMR signatures. Choline (Cho), N -acetylaspartylglutamate (NAA), along with lipids and lactate signatures are among those commonly altered in malignant brain tumors. Increased Cho is suggestive of an increase in cell turnover due to rapidly dividing cells. NAA, an intracellular neuronal marker, is commonly decreased in growing primary neoplasms. The ratio of Cho/NAA is commonly used as an NMR spectroscopic measure of malignant potential, with values higher than one indicative of a rapidly growing neoplasm. Lipid and lactate peaks, when present, are largely thought to reflect the degree of microscopic necrotic tissue composition, which can indicate an aggressive tumor. Other metabolites, including creatine and myo-inositol, ^, are also implicated in different malignant features or metabolic characteristics of different brain tumor subtypes.

Positron emission tomography. Molecular imaging using PET and radiolabeled tracers is rapidly becoming popular for serial assessment and diagnostic questions in patients with primary brain tumors. 2-[ F]-fluoro-2-deoxyglucose ( F-FDG) PET is the most common radiotracer used to detect malignant lesions in the body, and increased uptake of F-FDG is present in malignant gliomas (WHO grades III-IV) compared with low-grade gliomas (grade II). ^, Studies have shown elevated uptake of F-FDG in glioblastoma compared to contralateral normal brain, which has shown prognostic value with respect to time-to-progression (TTP). This change in F-FDG uptake can be detected within days of initiating radiochemotherapy ; however, no improvement in overall survival (OS) or progression-free survival (PFS) has been demonstrated by targeting FDG-avid areas with supplemental radiation treatment, which may speak to the complexity in delineating treated tumor from normal tissue that also exhibits elevated glucose consumption. This high basal F-FDG uptake in normal brain is one of the primary disadvantages of using F-FDG PET clinically, as it has significantly lower specificity compared with other PET tracers. Amino acid and amino acid analog PET tracers comprise a fundamentally different category of molecular imaging agents that show elevated uptake in tumor tissue with low uptake in normal brain tissue, resulting in higher specificity for delineating tumor. ^, The most common and most widely studied amino acid tracer is C-methionine ( C-MET) ; however, the short half-life of C has resulted in increased use of F-labeled amino acid analogs, including O -(2-[ F]-fluoro-ethyl)-l-tyrosine ( F-FET) and 3,4-dihydroxy-6-[ F]-fluoro-l-phenylalanine ( F-FDOPA). The uptake of F-FET and F-FDOPA has been reported to be similar to C-MET, ^, suggesting results obtained using C-MET will be similar to those obtained with newer F-labeled amino acid analogs. Although F-FDG and amino acid tracers constitute the majority of PET tracers used in routine clinical practice, the use of less routine PET tracers also show promise, including 3′-deoxy-3′-[ F]-fluorothymidine ( F-FLT) to visualize tumor regions undergoing proliferation or [ F]-fluoro-misonidazole ( F-FMISO) for visualizing hypoxic tumor regions.

Gliomas

The World Health Organization (WHO) classifies primary nervous system tumors into grades I to IV in order of increasing malignancy and worse prognosis. According to the WHO classification, gliomas can be divided into either diffuse or localized subtypes, for which diffuse gliomas can be further subdivided into astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas, depending on the particular histologic features of the tumor. Glioblastoma, or grade IV astrocytoma, can be subdivided into primary and secondary glioblastoma. Secondary glioblastomas arise from malignant transformation of grade II/III gliomas, as opposed to primary glioblastomas, which arise de novo. Ependymomas and choroid plexus tumors, which are also considered of glial origin, constitute most of the remaining proportion of primary brain tumors in adults.

Astrocytoma

Astrocytomas (WHO grade II) are diffusely infiltrative gliomas composed of neoplastic astrocytes. Astrocytomas typically have ill-defined boundaries, low cellularity, and few nuclear atypia. ^, Lacking malignant features such as endothelial microvascular proliferation, high mitotic activity and proliferation rate, and microscopic necrosis, astrocytomas are typically of low aggressivity compared to higher-grade tumors. Postcontrast T1-weighted MR images of low-grade astrocytomas typically lack contrast enhancement, as contrast uptake is indicative of blood–brain barrier compromise commonly caused by microvascular proliferation, characteristic of malignant transformation. Diffusion MR estimates of apparent diffusion coefficient (ADC), a measure of water mobility inversely proportional to cell density and proportional to extracellular space, is often low in distinct regions thought to contain viable tumor, while elevated in regions of infiltration and/or edema.

Anaplastic astrocytoma

Anaplastic astrocytomas (WHO grade III) are malignant astrocytomas with many of the histologic features of grade II astrocytomas, but lacking the endothelial microvascular proliferation and necrosis found in glioblastoma (WHO grade IV) tumors. Anaplastic astrocytomas are typically more highly cellular compared to low-grade astrocytomas and exhibit mitotic activity (Ki-67), typically of 12%–14%. ^, Increased cytoplasmic pleomorphism and elevated cellularity in anaplastic astrocytomas manifest as lower mean ADC values compared with low-grade astrocytomas, whereas slightly higher cerebral blood volume is also observed in high- compared to low-grade astrocytomas. Anaplastic astrocytomas typically demonstrate a higher degree of infiltrative features on standard and advanced magnetic resonance imaging (MRI) compared to low-grade astrocytomas, including blurring of the gray–white matter interface, and have higher rates of enhancement ( Figure 23-2 ).

Oligodendroglioma

Oligodendrogliomas (WHO grade II) comprise 2.1% of all primary brain and CNS tumors and 6.6% of all primary brain and CNS gliomas. Oligodendrogliomas occur approximately three times more often in white compared with black patients, and occur most often in the fourth and fifth decades of life. Almost two-thirds of patients with oligodendrogliomas present with seizures. Oligodendrogliomas are often gelatinous masses that tend to blur the white–gray matter interface on anatomic MRI. Oligodendrogliomas also often exhibit cystic degeneration and necrosis on MRI ( Figure 23-3 ). Calcifications within oligodendrogliomas are often detectable as hypointensities on gradient recall echo (GRE) or susceptibility-weighted MRI sequences, while presenting as hyperdensity on computed tomography (CT). Similar observations on MRI are also common because of hemorrhages within oligodendrogliomas. Histologically, oligodendroglioma tumor cells have indistinct cytoplasm and round nuclei, giving them a “fried egg” appearance, and are often distributed along regions of neovascularization with distinctive vascular patterns or “chicken wire” patterns. These geometrically distinct vascular patterns manifest as elevated blood volume on perfusion imaging compared with the same-grade astrocytomas, and the tightly packed oligodendroglioma tumor cells often result in a lower ADC compared with astrocytomas. Grade II oligodendrogliomas do not present with histopathologic features of anaplasia or malignant transformation; therefore, these tumors may have low a mitotic index (Ki-67) between 2% and 5%.

Anaplastic oligodendroglioma

Anaplastic oligodendrogliomas (WHO grade III) often occur as a result of anaplastic transformation of oligodendroglioma WHO grade II tumors, but can also occur de novo. Although they maintain many of the histologic features of low-grade oligodendrogliomas, anaplastic oligodendrogliomas have additional malignant features including increased mitotic activity, endothelial cell proliferation, microscopic necrosis, increased nuclear and cytoplasm pleomorphism, and tumor cell infiltration. Anaplastic oligodendrogliomas have both better clinical and prognostic outcomes compared to anaplastic astrocytomas, primarily because of the increased chemosensitivity in oligodendrogliomas. ^,

Glioblastoma

Glioblastoma, previously referred to as glioblastoma multiforme (GBM) , are the most malignant and most common primary brain tumors, constituting nearly 54% of all primary gliomas. Glioblastomas occur most frequently in older patients, and patterns in glioblastoma location suggest that the most frequent region of tumor occurrence moves from anterior to posterior with increasing age. Glioblastomas are highly infiltrative, proliferative, and aggressive brain tumors with a very poor patient prognosis. Despite advances in surgical resection, radiotherapy, and chemotherapy, median survival for patients with glioblastoma is around 14.6 months (radiotherapy and temozolomide) and 12.1 months for radiotherapy alone. Microscopically, glioblastomas exhibit many of the malignant features of anaplastic gliomas, with the addition of endothelial microvascular proliferation and pseudopalisading necrosis. Anatomic MRI exhibits contrast enhancement on postcontrast T1-weighted images in the majority of cases, and this contrast enhancement often occurs in a “ring-shape” enhancement with an area of central T1 hypointensity indicative of macroscopic necrosis. Perfusion imaging demonstrates elevated blood volume and blood flow in regions of contrast enhancement, corresponding to regions with elevated angiogenesis. T2-weighted or fluid-attenuated inversion recovery (FLAIR) images often show extensive tumor infiltration, along with “fingers of edema” presented as hyperintense regions on T2-weighted images respecting the gray–white matter interface at the cortical ribbon. T2-isointense or T2-hypointense regions within T2-hyperintense regions may signify dense bulk tumor regions in glioblastoma ( Figure 23-4 ).

Surgical planning and guidance

Imaging plays a large role in current surgical planning and intraoperative guidance for the treatment of gliomas. A number of imaging techniques are useful in surgical management of patients with gliomas. fMRI, MRI with diffusion tensor imaging (DTI), intraoperative monitoring, and image-guided needle biopsies are all useful in planning and execution. The overall goal of imaging is to assist the surgeon in obtaining a maximal resection while preventing neurologic complications . Extent of resection has been shown to correlate with overall survival.

Preoperative fMRI is used to localize critical areas involved in learning, memory, speech, motor, and sensory function. ^, fMRI testing maps areas of basic functions with regard to the tumor location. Mass effect from tumor or edema can distort the normal architecture of the brain, making localization by traditional landmarks difficult. fMRI facilitates surgical planning by localizing areas of eloquent cortex prior to surgery.

MRI with DTI provides information about major white-matter tracks associated with eloquent cortex ( Figure 23-5 ). It can determine if tumor is displacing critical white-matter tracks, enabling the surgeon to resect the tumor without causing significant neurologic deficits. Whereas fMRI helps the surgeon avoid critical areas of the cerebral cortex, MRI with DTI identifies the major white matter pathways and connections, assisting the surgeon with resection in the white matter and avoiding major fiber tracts. Interoperative MRI can account for brain shift that occurs during surgery, either from changes in pressure or resection of tumor. Image-guided needle biopsy provides real-time feedback on the location of the biopsy needle, increasing the accuracy of a blind needle biopsy to a few millimeters. These techniques minimize the potential for neurologic complications from surgery while helping the surgeon safely resect as much tumor as possible.

Treatment

Grade III gliomas

Treatment of anaplastic astrocytomas and anaplastic oligodendrogliomas is also similar. Again, much of the clinical management is dictated by expert consensus, and data from phase III studies is largely lacking. The initial treatment for grade III gliomas is gross total resection as assessed by routine MRI. When gross total resection is not possible, subtotal resection and biopsy are used for tissue diagnosis.

Following resection, treatment is most often 6 weeks of radiation therapy followed by chemotherapy. ^, Radiation therapy is fractionated into 30–33 treatments over 6 weeks. Chemotherapy is usually temozolomide, 5 days of treatment followed by 23 days off, for one 28-day cycle. Temozolomide was initially approved by the FDA for recurrent anaplastic astrocytomas. The PCV regimen of procarbazine, lomustine (CCNU), and vincristine have also been used. This regimen has been largely replaced by temozolomide alone, given the improved tolerability of temozolomide in comparison to PCV.

Patients are followed with serial MRI imaging, starting with the first postsurgical scan 2–6 weeks following radiation therapy, prior to the start of adjuvant chemotherapy ( Figure 23-6 ). Patients are monitored by MRI for response or progression every 2–4 months for 2–3 years, then less frequently afterwards. If recurrence is local, a second surgery can be considered, with or without the addition of carmustine (BCNU) wafers to the surgical cavity, followed by a change in the chemotherapy regimen. Reirradiation is also considered, especially if recurrent disease is outside the original field of radiation, but this is controversial.