**1. Introduction**

Glioblastoma Multiforme is the most malignant of gliomas. These malignancies that arise from glial cells remain one of the pre-eminent and confounding therapeutic challenges in oncology and medicine at-large. Though uncommon, it continues to be responsible for disproportionate rates of morbidity and mortality the world over, as qualified by a median survival of only about 15 months despite optimal treatment [1, 2]. This is in large part due to its heterogeneous biology, exceedingly complex molecular pathogenesis, and the tumor's predilection for growth in the CNS. Ongoing research, particularly in the last decade, has provided the scientific and medical worlds with ever deeper insight into, and further elucidation of, the biology and molecular pathogenesis of Glioblastoma Multiforme (GBM). This in turn has led to compelling novel treatment modalities that range from rudimentarily conceptual to, excitingly, on the very cusp of implementation. This chapter aims to provide the reader with a comprehensive survey of Glioblastoma Multiforme contextualized within the broader realm of malignant gliomas.

GBM is the most common malignant primary brain cancer in adults, accounting for roughly 3 new cases per 100,000 people [3]. Underscoring its importance as a therapeutic target, GBM accounts for nearly 16% of all brain tumors and, furthermore, nearly 46% of malignant gliomas [3]. The average age at diagnosis of GBM is 64 years of age, and, for reasons yet unclear, it has demonstrated a clear male predilection, being about 1.6 times more common in males than females [3].

Running in tandem with the quest for more effective therapies for GBM has been a long and intensive search for clear risk factors positively associated with the development of GBM. This search, however, has been fraught with many dead ends. Indeed, no clear inciting cause has been identified for the vast majority of cases of GBM and the only bona-fide established risk factor is exposure to ionizing radiation. The cause-effect relationship between ionizing

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radiation and the development of GBM was established with studies that demonstrated that children treated with radiotherapy for malignancies like leukemia have a markedly increased risk for developing GBM [4]. Family history of cancer of any type also has a suggested association, being found in the family members of roughly 19% of patients diagnosed with GBM in one small study [5]. In a small minority, approximately 5%, of diagnosed primary brain tumors, there is the presence of genetically inherited syndromes (e.g. Neurofibromatosis Types I and II, Li-Fraumeni Syndrome, von Hippel-Lindau Syndrome, Turcot Syndrome, Tuberous Sclerosis), which suggests a putative genetic relationship [6]. As with other malig‐ nancies, it has also been suggested that viral infections, specifically by SV40, HHV-6, and CMV, may be associated with the development of GBM by tumorigenesis through integration of viral genetic material into normal DNA [7-10]. Another putative association that has garnered much in the way of publicity is the relationship between cell phone use and development of primary brain tumors. This is a weakly-supported association based on the aggregate epidemiological data on hand that deserves further study and follow-up in the years to come as cell phone use becomes more ubiquitous the world over [11,12].

**Localized Astrocytoma**

Pilocytic Astrocytoma

Pleomorphic Xanthoastrocytoma Subependymal Giant Cell Astrocytoma

WHO Grade II (Astrocytoma)

WHO Grade II (Oligodendroglioma\_ WHO Grade III (Anaplastic Astrocytoma) WHO Grade III (Anaplastic Oligodendroglioma) WHO Grade IV (Glioblastoma Multiforme)

**Table 1.** WHO Classification of Gliomas

**Figure 1.** Gross Appearance of GBM

Giant Cell Glioblastoma

Gliosarcoma

**Diffuse Astrocytomas/Oligodendrogliomas**

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WHO Grade I

Fibrillary Protoplasmic Gemistocytic

#### **2. Histopathology**

GBM is, in a manner of speaking, the pathological culmination of and histological end point on the broader continuum of gliomas/astrocytomas. The word Glioma literally translates in Greek into the English equivalent of "glue" [13]. This connotates the functional conception of the cells that beget gliomas, i.e. gliomas arise from those cells in the CNS that form the support framework for neurons. It merits a side note here that though this has been the traditional conception of glial cells, new studies have shown them to possess a more autonomous role than previously supposed [15]. The WHO has classified gliomas/astrocytomas into 4 grades that, successively, convey graver prognostic significance (See Table 1); this is the 4th iteration of this classification system published in 2007 and originally conceived in 1979 [15]. This method of classification, based on histopathological features, is one that has built a certain assumed relevance for clinical decision making. The neuro-oncologist uses it as a template to guide whether a patient may qualify for a conservative strategy of watchful waiting, as with Grades I and sometimes with Grade II, or aggressive radiotherapy with chemotherapy, as with Grades III and IV. Indeed, only Grades III (Anaplastic astrocytoma/oligodendroglioma) and IV (GBM) are considered malignant gliomas. There are discrete histological features that qualify Grade III and IV astrocytomas as malignant. Grade III gliomas when compared to lower grades, is distinguished by a significant increase in cellularity, mitotic activity, and nuclear atypia [16] (See Figure 3). Grade IV gliomas, in addition to these telltale harbingers of malignant transformation, is embodied, uniquely, by areas of microvascular proliferation and/or neoplastic tissue necrosis [16] (See Figure 4). Indeed, it is worthy of emphatic mention that one of the overarching and typifying characteristics of malignant gliomas is their histological heterogeneity, i.e. consisting of both neoplastic and stromal tissue [16]


Gliosarcoma

radiation and the development of GBM was established with studies that demonstrated that children treated with radiotherapy for malignancies like leukemia have a markedly increased risk for developing GBM [4]. Family history of cancer of any type also has a suggested association, being found in the family members of roughly 19% of patients diagnosed with GBM in one small study [5]. In a small minority, approximately 5%, of diagnosed primary brain tumors, there is the presence of genetically inherited syndromes (e.g. Neurofibromatosis Types I and II, Li-Fraumeni Syndrome, von Hippel-Lindau Syndrome, Turcot Syndrome, Tuberous Sclerosis), which suggests a putative genetic relationship [6]. As with other malig‐ nancies, it has also been suggested that viral infections, specifically by SV40, HHV-6, and CMV, may be associated with the development of GBM by tumorigenesis through integration of viral genetic material into normal DNA [7-10]. Another putative association that has garnered much in the way of publicity is the relationship between cell phone use and development of primary brain tumors. This is a weakly-supported association based on the aggregate epidemiological data on hand that deserves further study and follow-up in the years to come as cell phone use

GBM is, in a manner of speaking, the pathological culmination of and histological end point on the broader continuum of gliomas/astrocytomas. The word Glioma literally translates in Greek into the English equivalent of "glue" [13]. This connotates the functional conception of the cells that beget gliomas, i.e. gliomas arise from those cells in the CNS that form the support framework for neurons. It merits a side note here that though this has been the traditional conception of glial cells, new studies have shown them to possess a more autonomous role than previously supposed [15]. The WHO has classified gliomas/astrocytomas into 4 grades that, successively, convey graver prognostic significance (See Table 1); this is the 4th iteration of this classification system published in 2007 and originally conceived in 1979 [15]. This method of classification, based on histopathological features, is one that has built a certain assumed relevance for clinical decision making. The neuro-oncologist uses it as a template to guide whether a patient may qualify for a conservative strategy of watchful waiting, as with Grades I and sometimes with Grade II, or aggressive radiotherapy with chemotherapy, as with Grades III and IV. Indeed, only Grades III (Anaplastic astrocytoma/oligodendroglioma) and IV (GBM) are considered malignant gliomas. There are discrete histological features that qualify Grade III and IV astrocytomas as malignant. Grade III gliomas when compared to lower grades, is distinguished by a significant increase in cellularity, mitotic activity, and nuclear atypia [16] (See Figure 3). Grade IV gliomas, in addition to these telltale harbingers of malignant transformation, is embodied, uniquely, by areas of microvascular proliferation and/or neoplastic tissue necrosis [16] (See Figure 4). Indeed, it is worthy of emphatic mention that one of the overarching and typifying characteristics of malignant gliomas is their histological

heterogeneity, i.e. consisting of both neoplastic and stromal tissue [16]

becomes more ubiquitous the world over [11,12].

4 Tumors of the Central Nervous System – Primary and Secondary

**2. Histopathology**

#### **Table 1.** WHO Classification of Gliomas

**Figure 1.** Gross Appearance of GBM

The pathology of GBM, quite simply, is summated by foci of necrotic tissue surrounded by anaplastic cells and microvascular hyperplasia. The anaplastic cells surrounding the foci of necrosis are unique for malignant gliomas and are known as "pseudopalisading cells" due to their configuration around the necrotic foci (Refer to asterisk in Figure 4, which shows a necrotic center surrounded by pseudopalisading cells). It is interesting to note that the pseudopalisades, hyperplastic vasculature and necrotic centers are all inextricably linked to one another. The pseudopalisading cells are found to be severely hypoxic which causes overexpression of hypoxia-inducible factor (HIF-1) and secretion of pro-angiogenic factors VEGF and IL-8. It is thought that the telltale hypoxia and necrosis that distinguish malignant gliomas arise as a result of vascular occlusion and intravascular thrombosis that are inevitable conse‐ quences of tumor outgrowing blood supply. By this model, then, the pseudopalisading nuclei are seen as waves allowing for tumor cells to extend outwards from necrotic foci into normal surrounding parenchyma [33]. Another tumor type of neuroepithelial tissue with malignant capacity is oligodendroglioma. This type of tumor usually presents in younger patients within the white matter of the frontal and temporal lobes. Histologically, oligodendrogliomas are characterized by round nuclei and perinuclear halos dispersed in a monotonous pattern. The perinuclear halos are a preparation artifact that is characteristic of oligodendrogliomas and are frequently described as having a "fried-egg appearance". This type of tumor can be classified as WHO grade II or III (diffuse oligodendroglioma and anaplastic oligodendroglio‐ ma respectively) and the presence of a high mitotic rate (most 5-10%), vascular endothelial hyperplasia and nuclear pleomorphism categorizes the tumor as Grade III anaplastic oligo‐

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When one considers the origin of malignant gliomas, i.e. the inciting events that herald transformation of normal glial tissue/parenchyma into malignant tissue, they conform to the general oncological orthodoxy. That is, they are basically the end-result of stepwise mutations in genes responsible for essential biological processes, most notably cell growth, proliferation and controlled cell death. Oncogenesis of GBM is essentially representative of that basic canon in oncology--activation of oncogenes and silencing of tumor suppressor genes. In other words, stepwise acquisition of new biological properties/characteristics by oncogenesis confers phenotypic characteristics that allow the malignant cells to outcompete their wild-type

Upon diagnosis, GBM is customarily delineated into one of two broad categories--Primary GBM, which arises *de novo* in brain tissue, or Secondary, which develops from lower grade astrocytomas (Refer to Table 2 for salient respective features and differences). In addition to the fundamental etiological difference, primary GBM possesses categorically different genetic and epigenetic differences from Secondary GBM. (Epigenetics refers to those meiotically or mitotically heritable traits resulting in phenotypic/gene expression patterns not related to changes in the underlying actual DNA code.) The vast majority of cases are GBM are primary, i.e*. de novo,* and comprise upwards of 90% of diagnosed cases. Epidemiologically, Primary

dendroglioma.

counterparts in their micro-mileu.

**3. Primary vs. secondary GBM**

**Figure 2.** Gross Appearance of GBM

**Figure 3.** Histological Appearance of Grade III Anaplastic Oligodendroglioma. [16]

**Figure 4.** Histological Appearance of GBM. First Panel shows Pseudopalisading Nuclei at area of asterisk; second panel shows mitotic figures at arrows and endothelial proliferation at asterisk. [16]

The pathology of GBM, quite simply, is summated by foci of necrotic tissue surrounded by anaplastic cells and microvascular hyperplasia. The anaplastic cells surrounding the foci of necrosis are unique for malignant gliomas and are known as "pseudopalisading cells" due to their configuration around the necrotic foci (Refer to asterisk in Figure 4, which shows a necrotic center surrounded by pseudopalisading cells). It is interesting to note that the pseudopalisades, hyperplastic vasculature and necrotic centers are all inextricably linked to one another. The pseudopalisading cells are found to be severely hypoxic which causes overexpression of hypoxia-inducible factor (HIF-1) and secretion of pro-angiogenic factors VEGF and IL-8. It is thought that the telltale hypoxia and necrosis that distinguish malignant gliomas arise as a result of vascular occlusion and intravascular thrombosis that are inevitable conse‐ quences of tumor outgrowing blood supply. By this model, then, the pseudopalisading nuclei are seen as waves allowing for tumor cells to extend outwards from necrotic foci into normal surrounding parenchyma [33]. Another tumor type of neuroepithelial tissue with malignant capacity is oligodendroglioma. This type of tumor usually presents in younger patients within the white matter of the frontal and temporal lobes. Histologically, oligodendrogliomas are characterized by round nuclei and perinuclear halos dispersed in a monotonous pattern. The perinuclear halos are a preparation artifact that is characteristic of oligodendrogliomas and are frequently described as having a "fried-egg appearance". This type of tumor can be classified as WHO grade II or III (diffuse oligodendroglioma and anaplastic oligodendroglio‐ ma respectively) and the presence of a high mitotic rate (most 5-10%), vascular endothelial hyperplasia and nuclear pleomorphism categorizes the tumor as Grade III anaplastic oligo‐ dendroglioma.

When one considers the origin of malignant gliomas, i.e. the inciting events that herald transformation of normal glial tissue/parenchyma into malignant tissue, they conform to the general oncological orthodoxy. That is, they are basically the end-result of stepwise mutations in genes responsible for essential biological processes, most notably cell growth, proliferation and controlled cell death. Oncogenesis of GBM is essentially representative of that basic canon in oncology--activation of oncogenes and silencing of tumor suppressor genes. In other words, stepwise acquisition of new biological properties/characteristics by oncogenesis confers phenotypic characteristics that allow the malignant cells to outcompete their wild-type counterparts in their micro-mileu.
