Clinical Presentation and Molecular Diagnosis of Glioma

Figure 1. Glioblastoma multiforme (GBM) shown on an MRI scan.
Image Unavailable
Mass found in the left side of the image represents a GBM lesion.
Adapted from “Fighting Cancer with Cancer”.
Retrieved from URL:
http://blogs.lt.vt.edu/jennasack/2013/03/27/fighting-cancer-with-cancer/

Brain tumours are neoplasms that primarily arise from cells of the brain parenchyma. Brain tumours that arise from glial cells, or gliomas, account for more than 70% of all brain tumours in humans, with glioblastoma multiforme (GBM) being the most common (Figure 1). GBM is a neoplasm that arises from astrocytes, though all glial cell types may give rise to a glioma [1-2]. Population studies have indicated GBM is also the most malignant brain tumour, with a less than 3% 5 year survival rate [3]. Gliomas can be either primary (de novo) or secondary. Primary gliomas arise from mutations in normal glial cells that lead to oncogenesis of the cell, and show no evidence of having arose from a less malignant precursor lesion or neoplasm. Secondary gliomas can arise from lower grade (discussed below) non-malignant tumours already present and acquire malignant characteristics [4]. Gliomas can be diagnosed mainly by radiology or histology. In general, histological classification is the best way to currently diagnose a glioma [5]. Most symptoms upon physical examination do not specifically identify any type of glioma (or any CNS neoplasm for that matter), making it difficult to diagnose a patient based on physical examination alone. Physical symptoms however depend on different factors such as the location of the tumour and age of those affected. Newer molecular methods could potentially be used to distinguish glioma subtypes, predict patient outcome and provide mechanistic insight into the pathology of the disease.

Clinical Presentation and Symptoms

Focal and Non-Focal Symptoms

Brain tumours can cause virtually any type of neurological symptom [6]. Symptom progression is gradual however, helping to distinguish a brain tumour from a static or slowly progressing diseases such as neurodegenerative disorders or rapidly progressive diseases like infections of the nervous system [2]. Symptoms can be nonspecific and have a global manifestation, such as headache, nausea or vomiting. Since tumour growth in the brain parenchyma causes elevated intracranial pressure (ICP), and this results in headache, it is a frequent symptom in patients that present with brain tumours. Of note however, while headaches are the most common symptom, they rarely present in isolation [2]. Moreover, elevated ICP is more likely occur when one is lying down as opposed to standing, and thus early morning headaches are common in patients with this type of cancer [7].

Symptoms can also be focal and specific to a brain region, for example those affected may exhibit visual or somatosensory loss, aphasia and dysphagia [8]. These tumours being localized to a specific region in the brain, can affect functions controlled by the brain regions they occupy. Localized slower growing gliomas (see low grade gliomas below) may be present for years before diagnosis, and focal seizures may occur for long periods of time without the patient noticing [2]. Also, gliomas predictably cause visual field loss when found in the occipital lobe, seizures when found in the temporal or frontal lobes, aphasia when located near Wernicke’s and Broca’s areas as well as hormonal imbalances when present in the area of the hypothalamus or pituitary [9].

In general however, symptoms arising from these neoplasms may not even be common to a cancer diagnosis. In some cases, central nervous system (CNS) tumours present with signs frequently observed in less serious disorders such as gasteroenteritis, migraines and behavioural disorders [9-10]. It is usually not possible to diagnose a specific type of brain tumour, including a glioma, solely from a physical examination. Thus, symptoms can vary depending on the size, location and growth rate of the tumour.

Histological Presentation and Diagnosis

The gold standard by which gliomas are diagnosed is by histopathology [1,5]. Each glioma is described by guidelines set out by the World Health Organization (WHO) [11]. The guidelines define central nervous system tumours (including gliomas) by their histological and prognostic attributes. While the guidelines describe all central nervous system tumours, including gliomas, tumours are graded based on factors such as the presence of atypical cells, capacity to undergo mitosis, endothelial proliferation and necrosis. Grades III and IV tumours are generally more malignant, and have two or more of the aforementioned criteria, while tumours graded I-II have one or less [12].

Location Specific Presentation

Figure 2. The Tentorium Cerebelli.
Image Unavailable
Tumours located above the tentorium are referred to as supratentorial
and are more common in adults, while tumours found below are called
infratentorial and are more common in children. Adapted from “Tentorium cerebelli”
Retrieved from URL:
http://en.wikipedia.org/wiki/Tentorium_cerebelli and
http://training.seer.cancer.gov/ss_module00_bbt/unit02_sec04_c_brain.html

Frequently, tumours are also characterized by their location in the brain parenchyma. Supratentorial tumours are located above the tentorium cerebelli, and infratentorial tumours are located below this border (Figure 2) [13]. The location of a glioma with respect to the tentorium differ between children and adults. About 70% of gliomas in adults are supratentorial, while 70% of childhood gliomas are infratentorial [14].

Age Specific Presentation

Finally, age is a prognostic factor in people with glioma. The average age for onset of all primary brain tumours (malignant or not) is 57 years [2]. Although gliomas in general occur mainly in later adulthood, they are distinct from gliomas of childhood. For example, brainstem gliomas are rare in adults but comprise a majority of childhood gliomas [8]. They are also of a lower grade (WHO classification) in adults than the same tumour in children. Strikingly, brainstem gliomas account for only 1-2% of all adult gliomas, as opposed to 10-20% in children, and have a median survival of less than one year in childhood [15-16].

Despite these diagnostic features, some gliomas remain poorly understood due to a number of factors. A tumour classified under a specific subtype (for example, pilocytic astrocytoma) may show incredible diversity within the neoplastic cells that make up the tumour, and tumours across subtypes can have overlapping morphological characteristics, making a definitive diagnosis difficult [17]. Further, gliomas remain largely incurable and advances in neuroimaging, radiation as well as chemotherapy have produced a modest increase in survival rates [5].In addition to being incurable, gliomas are extremely malignant, with some subtypes exhibiting a less than 1 year median survival rate [16]. Thus, new biomarkers and diagnostic techniques are expected to improve clinical management of the disease (that is, an earlier diagnosis to provide better patient outcome).

Molecular Diagnostics

Figure 3. Common genetic aberrations in gliomas.
Image Unavailable
Note that primary and secondary GBM both have chromosome 10q loss as a
major contributor to their development, but events such as PTEN loss is specific to only GBM. In addition,
common genetic alterations are shown correlated with a given WHO histological grade. The process by which
lower grade gliomas become more malignant and aggressive involves acquiring new genetic features.
Adapted from “Molecular Diagnostics of Gliomas” by
Nikiforova, M. N. & Hamilton, R. L. Molecular diagnostics of gliomas. Arch. Pathol. Lab. Med. 135, 558–68 (2011).

Current Molecular Diagnostic Tools

Currently gliomas can be characterized by molecular features that aid a physician in making a diagnosis. Only few molecular aberrations however, provide useful prognostic value for treating patients. Furthermore, there is heterogeneity among tumour cells that constitute a glioma with respect to their cellular characteristics. Evidences suggest there is even a variation in gene expression between histological types of glioma (that is, according to WHO type) [18]. This makes predicting the aggressiveness of a subtype based on cellular markers difficult. Various pathways are aberrant especially in malignant gliomas (for example, glioblastoma multiforme) including gene mutations, amplification and deletions of genes, chromosome irregularities and transcriptional interference [5,18].

Despite all this, some chromosomal abnormalities are associated with increased survival in conjunction with therapy. In de novo and secondary GBM, loss of the 10q chromosome are found in 60-70% of cases. The differentiating factor however, is that primary de novo or primary GBM has a more frequent loss of PTEN, a tumour suppressor lost in variety of other cancers (Figure 3) [18]. Allelic losses on chromosomes on 9p and 16q are associated with favourable clinical outcome in addition to radiotherapy for oligodendroglial and oligoastrocytic gliomas [17].

Though the mechanisms are not well defined, molecular links to anaplasia in some gliomas are well demonstrated. Anaplastic neoplasms are tumours in which the cells that comprise the neoplasm do not resemble normal cells in morphology or function [19]. In anaplastic gliomas, losses in chromosome 9p are frequent in addition to homozygous deletions of the CDKN2A/B gene, which encodes a cyclin dependent kinase [5]. While the antitumour function of CDK2A and B is unclear, studies indicate it is a tumour suppressor because it is lost in almost 70% of gliomas, and in addition its knockdown in multiple glioma cell lines causes an increase in malignant cell formation and proliferation [20]. Moreover, deletion of CDK2A can drive astrocytic cells to a more neural stem cell-like phenotype [21].

In summary, while molecular diagnostics could serve to identify some subtypes of glioma, the current approaches are at best correlational in predicting disease outcome (that is, they don’t reliably predict patient outcome on their own) and provide little insight into what is causing the cancer. Taking this into account, molecular techniques to better identify malignant glioma cells are necessary for a more complete diagnosis.

How Telomerase Prevents Chromosome Shorteningl
A video explaining the function of telomerase. Telomerase acts to prevent chromosome shortening by modifying
nucleoprotein caps at the end of a chromosome, which when degraded leads to cell senescence and death.
From <https://www.youtube.com/watch?v=vtXrehpCPEE>

A New Method of Diagnosis?

A recent study by Killela et al. may provide insight into future methods of molecular diagnosis in glioma. Killela et al. discuss the mechanisms by which telomeres are maintained in proliferating cells, and in this case, neural cancer cells [22]. Telomeres are nucleoprotein complexes at the end of a chromosome that help protect it from degradation (See video to the left for an explanation). During each cell division, they get shorter and when their length decreases below a threshold, cellular senescence or apoptosis is triggered [23]. Enzymes such as telomerase help maintain them through consecutive cells divisions and this prevents abnormal or premature cell senescence and death.

The authors suggest that the dysregulation of this process (towards increased activity) leads to cancer cells being able to evade these normal protective mechanisms. They note that unlike tumours that come from cells that are constantly renewed, in which telomerase activity is always high, tumours that arise from terminally differentiated cells such as glial cells (in which telomerase activity is low) harbor a mutation in the promoter region of a subunit of a cellular telomerase. Telomerase reverse transcriptase (TERT) is a catalytic subunit of the enzyme telomerase that is required to be present in order for telomerase to carry out its function. The authors show that mutations in the promoter region that lead to increased expression and thus increased activity of TERT, occur in a high number of adults with GBM (83%). Moreover, this is the most commonly occurring genetic mutation in GBM, and is in contrast with children, where the mutation is much less frequently found (11%). This correlated well with patient survival as well, as patients who did not have the over activating mutation survived 13 months longer on average when compared to those who did have the mutation (P=0.01) [22].

Interestingly, these findings potentially addresses a lot of issues with current diagnostic models. Firstly, mutations in the TERT promoter effectively distinguish between adult and childhood tumour types. This is important because the same glioma can have a completely different pathology in adults as opposed to children, as previously mentioned. It also fulfills the need of being specific to a subtype of a glioma as well. In the paper, only 3 glioma subtypes (all WHO grade II or higher) had >50% incidence of TERT promoter mutations in the population. Finally, it was a reliable predictor of patient outcome in the cohort studied. In combination with present histological grading, this can potentially provide a detailed prognosis for patients with glioma that is not currently available to physicians.

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