**3. Patient evaluation**

**GBMs** are typically large tumors at diagnosis. They occur most commonly in the supratentorial compartment and are less common in the posterior fossa and brainstem. Lesions usually start within the deep white matter, but often infiltrate into cortex (**Figure 1**), deep nuclei or through commissural pathways into the contralateral hemisphere.

When a GBM spreads across the corpus callosum, there is a characteristic appearance of bihemispheric involvement, resulting in the classic "butterfly" pattern on imaging (**Figure 2**).

The vast majority of GBMs are solitary lesions, but cases of multiple GBMs were observed in 0.5–1% of cases. Multiple gliomas can be categorized as multifocal or multicentric. Multifocal disease consists of multiple tumors which result from dissemination along an established route of CNS, spreading through white matter tracts, cerebrospinal fluid pathways or through local extension by satellite formations. They can be separated by abnormal white matter tracts within the same hemisphere (demonstrated by contiguous areas of modified T2-weighted signal on cerebral MRI (**Figure 3**).

On the other hand, multicentric disease represents multiple tumors with normal intervening brain, so widely separated masses in different lobes or hemispheres (**Figure 4**).

Although GBM is an invasive tumor, dissemination remains limited to the central nervous system and extracranial metastases are very rare (0.4–2%). GBMs usually appear like a mass with thick, irregular margins and a central necrotic core, sometimes with a hemorrhagic component. Tumors are surrounded by a vasogenic edema, characterized by extensive infiltration of tumor cells. This edema causes additional mass effect and leads to neurological disturbances.

The diagnosis of brain tumors must be evoked in any adult with symptoms of raised intracranial pressure, seizures or focal neurological deficit, the onset being usually weeks to months before. The **clinical presentation** is nonspecific and can vary widely, depending on the tumor localization and the rate of growth. Rarely, an intratumoral hemorrhage occurs and patient may present with sudden stroke-like symptoms. GBMs may occur at any age, but 70% of cases are seen between 45 and 70 years of age, with a mean age at the time of diagnosis being 53 years [10]. Men are more frequently involved (there is a sex ratio of 3:2).

All patients, who are presented with symptoms that could be caused by an intracranial mass, require **neuroimaging** to establish the cause of these symptoms. **CT scan** is often the first examination, because it is widely available, fast and inexpensive. Typical findings for GBM on CT scan are a heterogeneous mass lesion, with an isodense to slightly hyperdense irregular thick ring and a hypodense core representing necrosis. There is an intense, irregular and heterogeneous contrast enhancement of the tumor mass (**Figure 5**). Images highlight a significant surrounding cerebral edema and a marked mass effect. CT scan is helpful in demonstrating the presence of intratumoral hemorrhage or calcification, which is thought to be related to a

**Figure 2.** Butterfly glioblastoma – MRI features. Tumor involves both cerebral hemispheres by crossing the corpus callosum – Bifrontal localization. (a) Sagittal T1-weighted image with contrast; (b) axial T1-weighted image with contrast; (c) coronal T1-weighted image with contrast; (d) axial T2-weighted image; (e) sagittal fluid-attenuated inversion recovery

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 7

While CT scan provides initial data, **contrast-enhanced MRI** is the imaging modality of choice for GBMs, because of his greater accuracy and multi-planar imaging capabilities. All patients with a suspected brain tumor should have an MRI evaluation, unless it would be unsafe for them. It will confirm the diagnosis, will refine the diagnosis and will provide additional data needed for treatment planning. On T1-weighted images, GBMs typically appear as a hypo to isointense mass with central heterogeneous signal (necrosis, intratumoral hemorrhage and cysts), thick, irregular or poorly defined margins and peritumoral edema. After the administration of contrast medium, a heterogeneous or irregular ring-like enhancement is almost always present. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images reveal a heterogeneous, hyperintense mass with adjacent tumor infiltration/vasogenic edema.

pre-existing oligodendroglial lesion.

(FLAIR) sequence; (f) axial diffusion-weighted image (DWI).

**Figure 1.** Corticalized glioblastoma – Macroscopic appearance.

**3. Patient evaluation**

6 Brain Tumors - An Update

signal on cerebral MRI (**Figure 3**).

**GBMs** are typically large tumors at diagnosis. They occur most commonly in the supratentorial compartment and are less common in the posterior fossa and brainstem. Lesions usually start within the deep white matter, but often infiltrate into cortex (**Figure 1**), deep nuclei or

When a GBM spreads across the corpus callosum, there is a characteristic appearance of bihemispheric involvement, resulting in the classic "butterfly" pattern on imaging (**Figure 2**). The vast majority of GBMs are solitary lesions, but cases of multiple GBMs were observed in 0.5–1% of cases. Multiple gliomas can be categorized as multifocal or multicentric. Multifocal disease consists of multiple tumors which result from dissemination along an established route of CNS, spreading through white matter tracts, cerebrospinal fluid pathways or through local extension by satellite formations. They can be separated by abnormal white matter tracts within the same hemisphere (demonstrated by contiguous areas of modified T2-weighted

On the other hand, multicentric disease represents multiple tumors with normal intervening

Although GBM is an invasive tumor, dissemination remains limited to the central nervous system and extracranial metastases are very rare (0.4–2%). GBMs usually appear like a mass with thick, irregular margins and a central necrotic core, sometimes with a hemorrhagic component. Tumors are surrounded by a vasogenic edema, characterized by extensive infiltration of tumor cells. This edema causes additional mass effect and leads to neurological disturbances. The diagnosis of brain tumors must be evoked in any adult with symptoms of raised intracranial pressure, seizures or focal neurological deficit, the onset being usually weeks to months before. The **clinical presentation** is nonspecific and can vary widely, depending on the tumor localization and the rate of growth. Rarely, an intratumoral hemorrhage occurs and patient may present with sudden stroke-like symptoms. GBMs may occur at any age, but 70% of cases are seen between 45 and 70 years of age, with a mean age at the time of diagnosis being

brain, so widely separated masses in different lobes or hemispheres (**Figure 4**).

53 years [10]. Men are more frequently involved (there is a sex ratio of 3:2).

**Figure 1.** Corticalized glioblastoma – Macroscopic appearance.

through commissural pathways into the contralateral hemisphere.

**Figure 2.** Butterfly glioblastoma – MRI features. Tumor involves both cerebral hemispheres by crossing the corpus callosum – Bifrontal localization. (a) Sagittal T1-weighted image with contrast; (b) axial T1-weighted image with contrast; (c) coronal T1-weighted image with contrast; (d) axial T2-weighted image; (e) sagittal fluid-attenuated inversion recovery (FLAIR) sequence; (f) axial diffusion-weighted image (DWI).

All patients, who are presented with symptoms that could be caused by an intracranial mass, require **neuroimaging** to establish the cause of these symptoms. **CT scan** is often the first examination, because it is widely available, fast and inexpensive. Typical findings for GBM on CT scan are a heterogeneous mass lesion, with an isodense to slightly hyperdense irregular thick ring and a hypodense core representing necrosis. There is an intense, irregular and heterogeneous contrast enhancement of the tumor mass (**Figure 5**). Images highlight a significant surrounding cerebral edema and a marked mass effect. CT scan is helpful in demonstrating the presence of intratumoral hemorrhage or calcification, which is thought to be related to a pre-existing oligodendroglial lesion.

While CT scan provides initial data, **contrast-enhanced MRI** is the imaging modality of choice for GBMs, because of his greater accuracy and multi-planar imaging capabilities. All patients with a suspected brain tumor should have an MRI evaluation, unless it would be unsafe for them. It will confirm the diagnosis, will refine the diagnosis and will provide additional data needed for treatment planning. On T1-weighted images, GBMs typically appear as a hypo to isointense mass with central heterogeneous signal (necrosis, intratumoral hemorrhage and cysts), thick, irregular or poorly defined margins and peritumoral edema. After the administration of contrast medium, a heterogeneous or irregular ring-like enhancement is almost always present. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images reveal a heterogeneous, hyperintense mass with adjacent tumor infiltration/vasogenic edema.

**Figure 3.** Multifocal glioblastoma – MRI features. There are two separate tumor foci in the right frontal lobe: A smaller one in the basal frontal region and a bigger one in the anterior frontal region. The presence of connecting signal alteration in T2-weighted images defines multifocal lesions. (a) Coronal T1-weighted image with contrast, with section line at the level of smaller tumor; (b) axial T1-weighted image with contrast – Section level is indicated in (a); (c) axial T2-weighted image – Section level is indicated in (a); (d) coronal T1-weighted image with contrast, with section line at the level of bigger tumor; (e) axial T1-weighted image with contrast – Section level is indicated in (d); (f) axial T2-weighted image – Section level is indicated in (d).

Surrounding infiltrative edema (which is a combination of increased interstitial water and neoplastic cells) is better appreciated in T2-weighted images as compared with T1-weighted images (**Figures 5** and **6**).

Advanced imaging technologies have been developed, including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI) and MR spectroscopy (MRS). Diffusion-weighted imaging (DWI) allows the calculation of the apparent diffusion coefficient (ADC) that is correlated with tumor cellularity and tumor grade. Diffusion tensor imaging (DTI) offers the possibility to identify and to characterize the white matter tracts. Perfusion-weighted imaging (PWI) provides useful information about the cerebral microcirculation and allows the development of cerebral blood volume maps. MR spectroscopy (MRS) allows in vivo measurements of certain tissue metabolites. These techniques focus on pathophysiological changes in disease and offer potential indications on differential diagnosis and individual anatomy. Post-therapeutic MRI examinations are used to monitor treatment response and to differentiate radionecrosis from residual or recurrent tumor.

**Figure 4.** Multicentric synchronous glioblastoma – MRI features. There are widely separated lesions, occurring in different lobes or hemispheres, with no connection between foci. They were already present at the time of initial radiological investigation. The figures (a), (b), (c) and (d) demonstrate a left paraventricular occipital tumor: (a) axial T2-weighted image; (b) axial FLAIR sequence; (c) axial T1-weighted image with contrast; (d) sagittal T1-weighted image with contrast. The figures (e) and (f) illustrate a left posterior temporal lesion: (e) axial T2-weighted image; (f) axial FLAIR sequence. The figures (g) and (h) present a right deep temporal lesion: (g) axial T2-weighted image; (h) axial FLAIR sequence.The figures (i) and (j) reveals a left temporomesial lesion: (i) axial T2-weighted image; (j) axial FLAIR

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 9

sequence.

**Figure 4.** Multicentric synchronous glioblastoma – MRI features. There are widely separated lesions, occurring in different lobes or hemispheres, with no connection between foci. They were already present at the time of initial radiological investigation. The figures (a), (b), (c) and (d) demonstrate a left paraventricular occipital tumor: (a) axial T2-weighted image; (b) axial FLAIR sequence; (c) axial T1-weighted image with contrast; (d) sagittal T1-weighted image with contrast. The figures (e) and (f) illustrate a left posterior temporal lesion: (e) axial T2-weighted image; (f) axial FLAIR sequence. The figures (g) and (h) present a right deep temporal lesion: (g) axial T2-weighted image; (h) axial FLAIR sequence.The figures (i) and (j) reveals a left temporomesial lesion: (i) axial T2-weighted image; (j) axial FLAIR sequence.

Surrounding infiltrative edema (which is a combination of increased interstitial water and neoplastic cells) is better appreciated in T2-weighted images as compared with T1-weighted

**Figure 3.** Multifocal glioblastoma – MRI features. There are two separate tumor foci in the right frontal lobe: A smaller one in the basal frontal region and a bigger one in the anterior frontal region. The presence of connecting signal alteration in T2-weighted images defines multifocal lesions. (a) Coronal T1-weighted image with contrast, with section line at the level of smaller tumor; (b) axial T1-weighted image with contrast – Section level is indicated in (a); (c) axial T2-weighted image – Section level is indicated in (a); (d) coronal T1-weighted image with contrast, with section line at the level of bigger tumor; (e) axial T1-weighted image with contrast – Section level is indicated in (d); (f) axial T2-weighted image

Advanced imaging technologies have been developed, including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI) and MR spectroscopy (MRS). Diffusion-weighted imaging (DWI) allows the calculation of the apparent diffusion coefficient (ADC) that is correlated with tumor cellularity and tumor grade. Diffusion tensor imaging (DTI) offers the possibility to identify and to characterize the white matter tracts. Perfusion-weighted imaging (PWI) provides useful information about the cerebral microcirculation and allows the development of cerebral blood volume maps. MR spectroscopy (MRS) allows in vivo measurements of certain tissue metabolites. These techniques focus on pathophysiological changes in disease and offer potential indications on differential diagnosis and individual anatomy. Post-therapeutic MRI examinations are used to monitor treatment response and to differentiate radionecrosis from residual or recurrent tumor.

images (**Figures 5** and **6**).

– Section level is indicated in (d).

8 Brain Tumors - An Update

**Figure 5.** Left temporal glioblastoma. (a) CT scan without contrast; (b) CT scan with contrast; (c) MRI – Axial T2-weighted image; (d) MRI – Coronal FLAIR sequence; (e) MRI – Axial T1-weighted image with contrast; (f) MRI – Coronal T1-weighted image with contrast.

symptoms, making surgery safer. Anticonvulsants are necessary when a history of seizures exists. However, prophylactic use of antiepileptic drugs outside the perioperative phase is

**Figure 6.** Right temporal glioblastoma – MRI features. (a) Axial T1-weighted image; (b) axial T2-weighted image; (c) coronal FLAIR sequence; (d) axial T1-weighted image with contrast; (e) coronal T1-weighted image with contrast; (f)

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 11

Ideally, all patients with GBMs should be managed by a multidisciplinary team in a centralized neurosciences center. The neuro-oncology group should include specialists from neuroradiology, neurology, neurosurgery, neuropathology, intensive care, medical and radiation

Neuroimaging modalities provide a lot of data about mass lesion, but cannot reliably predict the diagnosis of tumor type and grade. Histological assessment is required. Thus, **a representative tissue sample should be obtained by biopsy or resection** to have a correct diagnosis before specific adjunctive therapies have been initiated. The neurosurgeon is involved in decision-making regarding the appropriate surgical procedure for patients with GBM. Based on preoperative evaluation, he must indicate either an open surgical resection for both diagnosis and treatment or only a biopsy for diagnosis. Special consideration should be given to some important factors, including age of the patient, location and size of the tumor, neurological status, functional impairment (quantified by Karnofsky Performance Status (KPS) Scale), significant comorbidity

controversial.

oncology, neurorehabilitation, etc.

sagittal T1-weighted image with contrast.

**4. Surgical management**

**Positron emission tomography (PET)** can be used to provide additional metabolic information of the tumor. This technique is based on the detection of radioactivity emitted by biochemically active molecules labeled with radiotracers. Different molecular processes can be investigated including glucose consumption, expression of amino acid transporters, proliferation rate, membrane biosynthesis and hypoxia. The glucose analog 18F-fluorodeoxyglucose (18F FDG) is the most commonly used radiotracer for PET to measure the local metabolic rate of glucose. Increased glucose metabolism is a feature of high-grade glioma (HGG) and a positive correlation between glycolysis rate and malignancy was demonstrated. Radiolabeled amino acids (like 11C Methionine—11C MET) have been introduced as suitable tracers in brain tumors, because amino acid transport as well as protein synthesis were both demonstrated to be enhanced in HGG. Even more, 11C MET has increased specificity and sensitivity, highlighting areas of cellular proliferation correlating well with the Ki-67 labeling index of proliferation and with microvascular density. PET can help distinguish GBMs from other brain lesions pre-operatively, can reveal malignant transformation in low-grade gliomas (LGG), and can evaluate the tumor extension for an appropriate site for biopsy, for surgery planning or for radiation therapy planning. PET is also important in assessment of treatment response, being beneficial for differentiation of tumor tissue from post-therapeutic changes.

In patients with a suspected diagnosis of GBMs, **initial management** is intended to control symptoms and prepare the patients for surgery. Corticosteroid therapy reduces peritumoral edema and alleviates symptoms of raised intracranial pressure and neurologic

**Figure 6.** Right temporal glioblastoma – MRI features. (a) Axial T1-weighted image; (b) axial T2-weighted image; (c) coronal FLAIR sequence; (d) axial T1-weighted image with contrast; (e) coronal T1-weighted image with contrast; (f) sagittal T1-weighted image with contrast.

symptoms, making surgery safer. Anticonvulsants are necessary when a history of seizures exists. However, prophylactic use of antiepileptic drugs outside the perioperative phase is controversial.

Ideally, all patients with GBMs should be managed by a multidisciplinary team in a centralized neurosciences center. The neuro-oncology group should include specialists from neuroradiology, neurology, neurosurgery, neuropathology, intensive care, medical and radiation oncology, neurorehabilitation, etc.
