**5. Diagnosis**

GBMs are almost always found in the elderly population with a mean age of diagnosis of 62 years and is characterized by a rapidly inexorable course till death [27]. The genetic/epigenetic features that beget the malignant transformation in primary GBM and encompass its difference from secondary GBM include: mutations in and amplification of EGFR, loss of heterozygosity of Chromosome 10q, deletion of the phosphatase and tensin homologue (PTEN) on Chromo‐ some 10, and p16 deletion [16,23]. Secondary GBM, on the other hand, predominantly affects younger patients with a mean age at diagnosis of 45 years, and is characterized by a much slower, more smoldering course than Primary GBM [23]. Secondary GBM evolves from Grade II (Low Grade Well-Differentiated) and Grade III (Anaplastic) astrocytomas, has a predilection for the frontal lobes, and develops from its precursors over the course of years. An epidemio‐ logical study from 2005 showed that the time of progression from low-grade astrocytoma to GBM was approximately 5.3 years whereas the time of progression from anaplastic astrocy‐ toma to GBM was approximately 1.4 years [28]. This stands in stark contrast to the rapidity of Primary GBM progression, with roughly two-thirds of patients having a clinical history from time of diagnosis to death of less than 3 months [27]. As stated, secondary glioblastoma has a genetic/epigenetic footprint that differs from Primary GBM, the exception being the common‐ ality of loss of heterozygosity of Chromosome 10q. The differences in this epigenetic footprint include: mutations in p53, over expression of Platelet-Derived Growth Factor Receptor (PDGFR), aberrancies in p16/Retinoblastoma pathways, and global differences in transcription patterns and DNA copy numbers [16]. It is worthy of emphatic mention here that primary and secondary GBM, though developing through distinct genetic and molecular pathways, are

**Primary GBM Secondary GBM**

grossly and histologically indistinguishable from one another.

8 Tumors of the Central Nervous System – Primary and Secondary

Mean Age at Diagnosis ~ 62 years of age ~45 years of age

The clinical presentation of GBM is, as intuited, dependent in large part on the location of the tumor. Continuing to bode ill for both treatment and prognosis is the sobering fact that malignant gliomas, and GBM in particular, grow insidiously and largely asymptomatically until they are big enough to elicit symptoms by sheer mass effect. By that time, tellingly, the options for surgical resection are relatively limited given extension into vital CNS parenchyma. Common presenting symptoms include recalcitrant headaches, unprovoked new-onset seizures, unprecedented memory loss, unaccountable changes in personality or consciousness, cognitive/language impairments, and other miscellaneous symptoms, i.e. nausea/vomiting.

Percentage of Cases > 90% < 10% Clinical Course Rapid Smoldering Genetic Hallmarks EGFR, etc. PDGFR, etc.

**Table 2.** Primary vs. Secondary GBM

**4. Clinical characteristics**

The diagnostic modalities for suspected GBM in the appropriate clinical setting are, broadly, twofold: imaging and biopsy. The cornerstone of imaging is MRI with and without Gadolinium contrast enhancement. Prior to administration of contrast, malignant gliomas are hypo-intense on T1-weighted images (See Figure 5). Upon administration of Gadolinium, it is found that tumor enhances heterogeneously; this allows it to be distinguished from surrounding edema that remains hypo-intense on T-1 weighted images (See Figure 5). Another ancillary MRI submodality is FLAIR (Fluid Attenuated Inverse Reconstruction) MRI (See Figure 5) [30]. The utility of FLAIR MRI is that, as an inversion recovery MRI technique, it can essentially nullify or subtract the effects of fluid, thereby suppressing CSF in brain imaging. This can be especially useful in planning radiation therapy (to be discussed in more detail below) when it is of vital importance to delineate malignancy from native vital brain parenchyma [31].

pathological diagnosis, palliation of mass effect, and some indication of improvement in survival [16]. Though rote surgical resection has remained somewhat limited due to the intricate insinuation of the tumor into brain tissue, new surgical technologies have allowed for more elegant and discriminating extrication of malignant tissue. One example is neuroendo‐ scopy, use of an endoscope deployed through the ventricles for a minimally-invasive approach to allow for biopsy, resection and alleviation of lesions causing obstructive hydrocephalus [13]. Another surgical technology is fluorescence-guided resection. This involves the administra‐ tion of a non-fluorescent prodrug 5-aminolevulinic acid (ALA) that, when taken up by tumor tissue, is converted to fluorescent metabolite protoporyphyrin IX (PpIX) and accumulates to a marked degree in Grade III and IV gliomas. The neurosurgeon intra-operatively deploys "blue light" which allows tumor tissue to be visualized as "red" due to the fluorescent biomarker. This, in turn, has been shown to allow for more optimal and extensive tumor

High Grade Glioma — Standard Approach, Obstacles and Future Directions

http://dx.doi.org/10.5772/58548

11

resection [13] (See Figure 6).

**Figure 6.** Flourescence/ALA-Guided Surgical Resection of GBM [13]

An important concept to invoke here in the discussion of surgical treatment is Extent Of Resection (EOR), i.e. the extent of tumor tissue that can be safely resected. There is, as would be intuited, a likely positive association between (EOR) and patient survival/patient outcome. Data from the ALA-glioma Study Group out of Germany provided the highest level of evidence--2b--for a positive association between patient outcome, i.e. progression free

**Figure 5.** (A) T1 pre-contrast images exhibit a hypointense lesion in the left frontal lobe region (arrow). (B) Axial T1 post-contrast images, after injection of 20 cc of intravenous MultiHance®, demonstrate a focus of enhancement in left frontal lobe. (C) Axial T2 FLAIR images show increase in FLAIR signal in the left frontal lobe, which demonstrates en‐ hancement. (D) T2 FSE images also demonstrate increase in signal in the region of the left frontal lobe.[30]

The gold standard for diagnosis, of course, remains procurement of tissue for histological confirmation that can either be accomplished either diagnostically through stereotactic biopsy or, more commonly, diagnostically and therapeutically with tissue samples obtained during craniotomy for the purposes of tumor resection or debulking.
