Brain malignancy

Though currently available clinical treatments and therapies have clearly extended the survival of patients with brain tumors, many of these advances are short lived, particularly with respect to high grade gliomas such as glioblastoma multiforme. The missing link to an efficacious treatment of high grade gliomas is a more complete understanding of the basic molecular and cellular origin of brain tumors. 

However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between benign and malignant cells within the central nervous system. Investigation of cancer stem cell hypothesis and brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely this promising new area of focus. 

“Molecular neurosurgery”, glioma treatments involving biologics using neural stem cells to target the cancer at the level of individual migratory cell, is a rapidly evolving field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions. 

Glioma model

Glioblastomas (GBM) are the most malignant solid tumours (grade IV) of CNS. They are glial lineage neoplasias with a high proliferative and invasive capacity, reaching to occupy an entire lobe of the brain . According with their genesis, they can be differentiated between primary and secondary glioblastoma.

The primary is the most common glioblastoma.This is a new generated tumour after a brief medical history (three months), with no evidence of a less malignant lesion. On the other hand, secondary glioblastoma develops from diffuse astrocytoma, anaplastic astrocytoma or oligodendroglioma and malignant progression. 

Its development time is about five years. It is thought that both types of glioblastomas may be generated from neoplastic cells with characteristic of stem cells (Ohgaki & Kleihues, 2009). In addition, these cancer stem cells called “glioma stem cells” (GSCs) may be the responsible for glioma recurrences due to chemo-and radio resistance.  Glioma stem cells (GSCs) are a subpopulation of neoplastic cells identified in glioma sharing properties with neural stem cells (self-renewal, high proliferation rate, undifferentiating, and neurospheres conformation) and the capacity for leading the tumourigenesis and tumour malignancy. 

The proliferation and the invasion into adjacent normal parenchyma have been attributed to glioma stem cells as well. Indeed, they were related to the angiogenesis process needed for the growth and survival of the neoplasia. The microvascular network in gliomas has to get adapt to metabolic tissue requirements . When the vascular network cannot satisfy cell requirements (Oxygen pressure of 5-10 mm Hg) tissue hypoxia occurs. This situation triggers the synthesis of proangiogenic factors as matrix metalloprotease (MMP-2), angiopoietin-1, phosphoglycerate kinase (PGK), erythropoietin (EPO), and vascular endothelial growth factor (VEGF)-A .

Vascular endothelial growth factor (VEGF) is a major regulator of tumour angiogenesis . VEGF acts as mitogen, survival, antiapoptotic and vascular permeability factor (VPF) for the endothelial cells . The increase of this pro-angiogenic factor, secreted either by neoplastic cells or by cells of the tumour microenvironment, induces the start of angiogenesis, the called “angiogenic switch”.

This event results in the transition from avascularised hyperplasia to outgrowing vascularised tumour and eventually to malignant progression. It has been shown in human glioma biopsies that VEGF overexpression correlates directly to proliferation, vascularization and degree of malignancy, and therefore inversely to prognosis . 

The synthesis of VEGF is mediated by the Hypoxia-Inducible Factor (HIF-1), a critical step for the formation of new blood vessels and for the adaptation of microenvironment to the growth of gliomas . Recent researches have reported that glioma stem cells play a pivotal role inducing the angiogenesis via HIF-1/VEGF . 

By the other hand, hypoxia has been related to clones selection of tumour cells. These clones adapted to the tumour microenvironment have acquired the phenotype of tumour stem cell with increased proliferative and infiltrative capacity . Invasion of adjacent normal parenchyma has been attributed to glioma stem cells as well.
Due to these evidences, GSCs are currently being considered as a potential therapeutic target of the tumours. Recent studies have been focused on the identification of GSCs. In human glioblastomas they have been identified using CD133 marker .

In addition to this, it has been reported that ENU glioma model is a representative model for human glioma due to its location and also to its similar cellular, molecular and genetic alterations  Our experience with this model has proven to be useful to study many aspects of tumourigenesis and neoangiogenesis. 

In previous researches we reported the progression of tumour malignancy associated with vascular structural alterations and blood brain barrier (BBB) disturbances . ENU induced glioma permitted us to identify tumour developmentstages following microvascular changes. In addition, it was possible to study the angiogenesis process. Recently, we have used this model to study the relationship between glioma stem cells and angiogenesis process during the neoplasia development.

Classification and genes

Most recent classifications of brain tumours build on the 1926 work of Bailey and Cushing.² This classification named tumours after the cell type in the developing embryo/fetus or adult which the tumour cells most resembled histologically. The cell of origin of the majority of brain tumours is unknown as no pre-malignant states are recognised, as is the case in some epithelial tumour forms. 

In some tumours, cells may be so atypical that it is difficult to compare them with any normal cell type—hence the use of terms such as glioblastoma. Many unsound or illogical terms have remained in the classifications, as once established in a complex medical setting they are difficult to change. In this paper the terminology and definitions of the World Health Organization classification of 2000 will be exclusively used.

There are more than 120 entities in this classification and here we will concentrate on those that most frequently occur in adults and children. These are the pilocytic astrocytomas, ependymomas, and medulloblastomas in children, and the diffuse astrocytic tumours (including astrocytoma, anaplastic astrocytomas, and glioblastomas), oligodendrogliomas, and meningiomas in adults. 

Tumours of the central nervous system often have a wide morphological spectrum and classification is dependent on the recognition of areas with the characteristic histology for a particular tumour type. Immunocytochemical methods may be required to demonstrate the expression by the tumour cells of an antigen typically expressed by a particular cell type and thus to assist in classification. Unfortunately there are no antibodies that unequivocally identify the different tumour types. The presence or absence of an antigen only adds a further piece of information helping to indicate the tumour type. 

Four malignancy grades are recognised by the WHO system, with grade I tumours the biologically least aggressive and grade IV the biologically most aggressive tumours. The histological criteria for malignancy grading are not uniform for all tumour types and thus all tumours must be classified before the malignancy grade can be determined. Only one or two malignancy grades can be attributed to some tumour types. Brain tumours are well known to progress, becoming more malignant with time. Such progression will initially be focal. A patient’s diagnosis is based on the most malignant part of the tumour. Thus it is of the utmost importance to sample the tumour adequately in order to determine its type and judge its malignant potential. It follows that malignancy grading on biopsies/stereotactic biopsies is always a minimum grading as more anaplastic regions may be present in non-biopsied areas.

Cytotoxic or radiation therapy before histological diagnosis may make classification and malignancy grading extremely difficult or impossible. The clinical implications of tumour classification and malignancy grading have been empirically determined. The application of objective methods of measuring cell proliferation and death in tumours to malignancy grading is conceptually attractive but have yet to be accepted and utilised in the malignancy grading of brain tumours. 

The MIB 1 antibody recognising the same antigen as Ki67 as well as other antibodies identifying antigens associated with proliferation (for example, Cdc6 and Mcm5) can be used efficiently on formalin fixed, paraffin embedded tissues following microwave antigen retrieval.

However, wide variations in the proliferation indices are observed in different areas of individual brain tumours and this has resulted in difficulties in defining relevant proliferation levels. The same applies to the assessment of the numbers of cells undergoing apoptosis. The advances in neuroradiology and parallel improvements in stereotactic and surgical techniques permit the biopsy of just about any neoplastic or non-neoplastic lesion in the central nervous system (CNS). The list of potential diagnoses is thus vast. 

The neuropathologist may be expected to make a diagnosis on the basis of often very small and fragmented biopsies. He thus needs to know the clinical background of the case. Information must be provided: age, neuroradiological findings including location of the tumour, relevant clinical and family history, and whether the patient has received any treatment, including steroids. 

As can be deduced from the above, morphology combined with immunocytochemistry may only provide a differential diagnosis and the most likely diagnosis will then only be reached by considering all the information available at a multidisciplinary team meeting. The vast majority of brain tumours are sporadic. A number of familial syndromes are well documented with an increased incidence of brain tumours (see table 1 and the references therein). However, even in the most common syndromes (neurofibromatosis type 1 and neurofibromatosis type 2), the precise relative risk is difficult to deffine.

Grade VII : Meningioma specimen malignancy

Typical meningioma specimen malignancy grade I showing an example of the common transitional meningioma with multiple whorles (a few marked with arrows). Meningiomas generally expand and displace but do not invade adjacent brain or spinal chord. Invasion of the dura and skull does occur and has no significance for malignancy grading. Invasion of the skull may elicit an osteoblastic reaction. Brain invasion can occur in meningiomas of all malignancy grades and indicates a greater likelihood of recurrence, but is not considered sufficient criteria alone to increase the malignancy grade. 

The higher incidence of meningiomas in women, the apparent manifestation of tumours during pregnancy, and the association of meningiomas with breast and genital cancer have suggested oestrogen and progesterone dependency of the tumours. Meningiomas generally express progesterone receptors and some cases also express oestrogen receptors. 

Meningiomas were one of the first solid tumours in humans to be shown to have consistent chromosomal abnormalities, the loss of one copy of chromosome 22.  The fact that the second most common tumour in neurofibromatosis type 2 patients was meningioma pointed to the NF2 gene as a target on chromosome 22. 

Loss of wild copy NF2 is found in roughly half of sporadic and the majority of NF2 associated meningiomas. In the sporadic cases this is usually by the loss of one copy (monosomy 22) and mutation of the retained copy. The NF2 gene encodes a protein known variously as merlinor schwannomen. This protein has been shown to be involved in control of cell growth and motility in culture.

Genetically engineered mice with only one wild-type allele have been shown to develop many tumour forms while tissue specific inactivation in Schwann cells or leptomeningeal cells results in schwannoma or meningioma formation, respectively.

As stated above meningiomas may progress from grade I tumours to tumours of higher malignancy grade. This is associated with losses on chromosomal arms 1p, 6q, 9p, 10p and q, 14q, 18q, as well as gains and some amplifications on many other chromosomes.  The genes targeted by these abnormalities are mostly unknown, but the losses on 9p are associated with loss of both wild-type copies of CDKN2A, p14ARF, and CDKN2B as is commonly seen in the de novo glioblastomas and anaplastic oligodendrogliomas.

CONCLUSIONS

 

The goal for all histopathology is to provide—on the basis of an analysis of the tissue received—as much useful information as possible to the clinician, informing him/her of all the details of any pathological process present, and forming the basis for the choice of the most appropriate treatment, and a judgement of prognosis. Up until relatively recently this process was mainly based on a morphological analysis. 

However, as different forms of treatment become more and more based on targeting molecular mechanisms, the analysis of the specimens received must be extended to provide relevant data. This has already occurred examples include determination of oestrogen receptor, or HER2 expression in breast cancer, which will determine whether the patient will benefit from tamoxifen or herceptin treatment. 

New technologies currently being introduced will permit a detailed analysis of the genome and transcriptosome of clinical material impossible in the past and the integration of genetic and expression data with the histological information. Eventually we can hope that the molecular information will provide the basis for specific treatments that will only annihilate brain tumour cells, leaving the brain and the rest of the patient unharmed.

Grade VI : Oligodendroglioma malignancy

Oligodendroglioma malignancy grade II (H&E) with the typical tumour cell morphology—round nuclei and swollen cytoplasm. Note the microcalcifications (arrows) mainly in the lower right of the field. This is a common feature in oligodendrogliomas but is not unique to this form of glioma.

Increases in nuclear pleomorphism and hyperchromatism, as well as pronounced hypercellularity, brisk mitotic activity, prominent microvascular proliferation, and/or spontaneous necrosis, results in a picture that is histologically classified as anaplastic oligodendroglioma (malignancy grade III). Anaplastic forms of oligoastrocytomas also occur and similar criteria are used to distinguish them from oligoastrocytomas. 

Since 1990, when combination chemotherapy (procarbazine, lomustin, and vincristine (PCV)) was demonstrated to result in sometimes a dramatic tumour response,  the identification of all forms of glioma with oligodendroglial components has become crucial. Oligodendrogliomas show relatively specific genetic abnormalities that differ from the other gliomas. Loss of genetic information from 1p and 19p was demonstrated in a genomic wide analysis in 1994 and this was later linked to a good response to PCV treatment, an association that is currently under intense scrutiny as it provides the first molecular indicator of treatment response in brain tumours.

  The losses on 1p and 19q are most common among the grade II oligodendrogliomas (reports of up to 90%) and are present in over 50% of anaplastic oligodendrogliomas (malignancy grade III). Despite the fact that almost 10 years has elapsed since the identification of these relatively specific losses the genes targeted on these two chromosomes are still unknown. 

Oligodendrogliomas grade II also show methylation of p14^ARF, over-expression of EGFR and both ligands and receptors of the platelet derived growth factor (PDGF) system. Malignant progression is associated with additional genetic abnormalities similar to those described above for the astrocytic tumours—that is, disruption of the Rb1 pathway due to homozygous deletions or in some cases hypermethylation of the CDKN2A/p14^ARF locus, or the RB1 locus or CDK4 amplification and overexpression as is also seen in the progression of the diffuse astrocytic tumours. 

Some anaplastic oligodendrogliomas have no wild-type PTEN although this is usually in tumours without 1p and 19q loss. Anaplastic oligodendrogliomas also have abnormalities of many other chromosomal regions including chromosomes 4, 6, 7, 11, 13, 15, 18, and 22. Oligoastrocytomas and anaplastic oligoastrocytomas tend to have either aberrant genetic patterns similar to the oligodendroglial tumours or the diffuse astrocytic tumours. As yet there are no specific abnormalities associated with these mixed glial tumours. 

Meningiomas

 

Meningiomas are usually solitary lobulated tumours arising in the meninges and attached to the dura. They are believed to develop from meningothelial (arachnoidal) cells, despite the fact that the meningothelial form is far from the most common. Symptomatic meningiomas represent 13–26% of primary intracranial tumours, are most common in middle aged and elderly patients, and show a pronounced female predominance. 

 

Small asymptomatic meningiomas are found incidentally in 1.4% of necropsies. Patients with NF2 and members of some other non-NF2 familial syndromes may develop multiple meningiomas, often early in life. Ionising radiation is a well recognised predisposing factor. The cellular morphology, growth pattern, and the presence of extracellular material allow differentiation into the various histological subtypes (fig 7). Meningiomas are graded as malignancy grade I, atypical meningiomas as malignancy grade II, and anaplastic meningiomas as grade III.

 

Meningeal sarcomas are WHO malignancy graded as IV. The vast majority (about 80%) of meningiomas are of malignancy grade I. Atypical meningiomas constitute less than 20% of meningiomas while anaplastic variants are unusual (< 2%). Both atypical and anaplastic meningiomas are more common in men. Meningiomas may progress and therefore should be thoroughly sampled to identify areas with a histology associated with a more aggressive behaviour. 

 

The histological criteria indicating a more aggressive behaviour and thus an increase in the malignancy grade include frequent mitoses, regions of hypercellularity, sheet-like growth, high nuclear–cytoplasmic ratio, prominent nucleoli, and spontaneous necrosis. The criteria for the different malignancy grades are strictly defined by WHO.

 

Some subtypes, characterised by particular tumour cell phenotypes, are associated with more frequent recurrence and they are now classified as malignancy grade II or III. For example, tumours with a papillary growth pattern or areas of rhabdoid cells (rounded tumour cells with an eccentric nucleus with nucleolus and a prominent eosinophilic cytoplasm) are classified as papillary and rhabdoid meningiomas, respectively (malignancy grade III) as they have been documented to behave in a very aggressive fashion.

 

 

 

Grade V : The Rb1 pathway

Simplified diagram of interactions between the proteins of the Rb1 pathway (above) and the p53 pathway (below). The genes coding for p16 and p15 proteins are CDKN2A and CDKN2B, respectively. The genes for all of the proteins underlined have been shown to be abnormal in the astrocytic and some other gliomas as well as many other tumour cell types in other organs.

In the vast majority of cases where a pathway is disrupted in a tumour it is due to only one of the genes coding for a protein in that pathway being abnormal (loss of both wild type copies in the case of most tumour suppressor genes or amplification and overexpression in the case of proto-oncogenes). Thus it appears that pathways are targeted in oncogenesis and progression, and can be disrupted in many ways by losing, mutating, or amplifying the genes coding for the protein components of the pathway. 

The numbers of cases of anaplastic astrocytomas (malignancy grade III) studied are also limited. Mutations of the TP53 gene also occur at approximately the same frequency as is found in the astrocytomas malignancy grade II. Thus in the anaplastic astrocytomas the p53 pathway is also non-functional, and in the majority of cases (more than 60%) this is due to mutations of the TP53 gene. Cytogenetics, CGH, and molecular genetic techniques all show that the losses of alleles on 6q, 13q, 17p and 22q, as seen in the astrocytoma malignancy grade II, occur at similar or higher frequencies in the anaplastic astrocytomas. 

With the sole exception of losses of alleles on 19q (targeted gene unknown) there are no conclusively demonstrated abnormalities specific to this malignancy grade. Around 20% of anaplastic astrocytomas show similar genetic abnormalities to those found in glioblastomas involving other components of the p53 pathway (that is, MDM2 and p14^ARF) and lead to disruption of the Rb1 pathway (fig 5), and these are discussed in the glioblastoma section below

De novo glioblastomas are common and this has ensured their study in considerable numbers. Secondary glioblastomas are less frequent and very less commonly studied. Such patients will frequently have been treated by irradiation and/or with cytotoxic drugs. Glioblastomas show the greatest numbers of genetic abnormalities among the astrocytic tumours and clear patterns of genetic aberrations are emerging. 

The p53 pathway in glioblastomas is targeted through mutation of the TP53 gene (approximately 37%), as is seen in astrocytomas and anaplastic astrocytomas, but also by targeting other genes coding for proteins that control cellular p53 levels. The two genes whose products are involved in controlling p53 levels are p14^ARF and MDM2. p14^ARF controls the activity of MDM2,  which in its turn controls the breakdown of p53.  

Loss of both copies of the p14^ARF gene or amplification and over-expression of MDM2 will lead to the rapid breakdown of wild type p53 protein resulting in a cell with little or no wild type p53. The vast majority of glioblastomas (> 70%) have either no wild type p53 or no p14^ARF or over express MDM2 as mutually exclusive genetic abnormalities. Methylation of the p14^ARF promoter with decreased or non-expression are further mechanisms that have been shown to be involved in some tumours. In glioblastomas additionally the retinoblastoma pathway and the PI3 kinase–Act pathway are also targeted. 

In a similar manner one or other of the genes coding for proteins involved in the control of entry into the S phase of the cell cycle (the retinoblastoma pathway) are mutated in glioblastomas (fig 1). Entry into S phase is normally initiated by the release of transcription factors from newly phosphorylated Rb1 at the restriction point in G₁. At the end of the cell cycle Rb1 is unphosphorylated. Unphosphorylated Rb1 normally sequesters the E2F transcription factors. 

 Loss of wild type RB1 gene resulting in no functional RB1 or inappropriately phosphorylated Rb1 will result in any expressed E2F being free to initiate transcription of the genes necessary for entry into S phase. Inappropriate phosphorylation may be achieved in glioblastomas with wild type Rb1 by either loss of wild type p16 expression or over-expression of CDK4 caused by amplification of its gene. These would make inappropriate phosphorylation of a wild type Rb1 more likely with the release of the E2Fs. p16 normally binds CDK4 and thus inhibits the formation of the CDK4/cyclin D1 heterodimer. 

 In the absence of p16 all expressed CDK4 is available for heterodimer formation. When CDK4 is overexpressed in the presence of normal levels of p16 there will be excess CDK4 available for heterodimer formation. One or the other of these abnormalities are present in over 90% of glioblastomas and are, with very few exceptions, mutually exclusive. 

 While disruption of the p53 and Rb1 pathways seem essential for glioblastomas, the ways in which the pathways are rendered dysfunctional may confer slightly different biological characteristics on the individual glioblastoma. In addition to the genetic abnormalities resulting in the disruption of the p53 and Rb1 pathways, over 90% of glioblastomas lose alleles from 10q. 

The regions consistently lost include the variously named PTEN/MMAC1/TEP1 tumour suppressor gene at 10q23–24. PTEN has been shown to be mutated in up to 45% of glioblastomas. The gene is a dual specificity phosphatase (necessary for its ability to function as a tumour suppressor) and has homology to the cytoskeletal protein tensin. 

 One of its major substrates is phosphatidylinositol-3, 4, 5-triphosphate (PIP3) and lack of control of PIP3 is likely to have a major effect on the activation of the Akt pathway, affecting among other things apoptosis and HIF-1 activity. 

 Other genes coding for proteins involved in the PI3K/AKT pathway have recently been shown to be mutated, albeit infrequently. This is supported by reports on the affect of Akt activation in an animal model of astrocytoma.

Amplification of the epidermal growth factor receptor (EGFR) gene (7p11–12) is found in about 35% of glioblastomas. When amplified this gene is always over-expressed but may also be over-expressed in glioblastomas without amplification. Rearrangements of the amplified gene occur in almost half of the tumours with amplification. 

The most common rearrangement results in a transcript that is aberrantly spliced, remains in frame,  and codes for a mutated EGFR that has lost 267 amino acids of its extracellular domain and does not bind ligand.  This mutated EGFR is constitutively activated and attempts are ongoing to target treatment to this aberrant cell surface molecule. 

Other rearrangements of the amplified EGFR gene occur less frequently and may result in abnormalities of the cytoplasmic domain Glioblastomas can develop from an astrocytoma or as a de novo glioblastoma. It is tempting to try to sort all these findings into a series of events explaining the development of the two forms of glioblastoma. 

Both have disrupted the normal p53 and Rb1 pathways, but in different ways. The de novo tumours do this by a single genetic event when amplification of the 12q14 region encompassing the CDK4 and MDM2 genes results in their over-expression and the disruption of both pathways. Two genetic events are required to disrupt the two pathways when homozygous deletion of the region on 9p encompassing the genes coding for p16 (CDKN2A), p15 (CDKN2B), and p14^ARF (p14^AR)) occurs (requires loss of both autosomes). 

Occasionally de novo tumours may also show more complex patterns of mutations with loss of one allele of each of TP53 and RB1, with mutation of the retained alleles, requiring four genetic mutational events. However, in de novo glioblastomas these are in the minority. 

Secondary glioblastomas generally have no wild type p53 due to loss of one allele and mutation of the retained allele, and lose a functional Rb1 pathway in a similar manner. Other correlations are that EGFR amplification is unusual in cases with no wild type p53, although this does occur occasionally. In addition to the abnormalities of the genes listed there are likely to be many other genetic changes affecting other regions of the genome that have been found to be manifestly abnormal in these tumours by deletion or amplicon mapping. The genes targeted by these changes have yet to be identified. 

Oligodendrogliomas

 

Oligodendrogliomas occur mainly in the cerebral hemispheres of adults. They are believed to derive from oligodendrocytes. They consist of moderately cellular, monomorphic tumours with round nuclei, often artefactually swollen cytoplasm on paraffin section (fig 6), few or no mitoses, no florid microvascular proliferation or necrosis, and are classified as malignancy grade II according to the WHO. 

Classically they show a “chicken wire” pattern of capillaries. They do not express any antigen characteristic of normal oligodendrocytes and may express GFAP. Grade II oligodendrogliomas are relatively indolent, although they usually recur at the primary site and may display a tendency for subependymal spread with a 5% incidence of cerebrospinal fluid (CSF) seeding. Oligoastrocytomas consist of tumour cells with either astroctytic or oligodendroglial morphological characteristics.

Tumour cells with these two phenotypes can be either diffusely mixed or combined as discrete areas in an individual tumour. The morphological borderlines between astrocytomas, oligoastrocytomas, and oligodendrogliomas are difficult and controversial issues.

Grade IV : Tumours of the astrocytic series (H&E)

Tumours of the astrocytic series (H&E). (A) Astrocytoma malignancy grade II (arrows pointing to thin walled tumour capillary vessels). (B) Anaplastic astrocytoma malignancy grade III demonstrating anaplastic tumour cells but with no evidence for microvascular proliferation (arrows; compare with A and C). (C) Glioblastoma with florid endothelial proliferation (arrows). 

Before reading the following section it is essential that fig 5 is first reviewed and referred to as necessary. Cytogenetic and molecular data are limited on astrocytomas (malignancy grade II) as they are not so common. Over 60% of astrocytomas (malignancy grade II) have loss of alleles on 17p, including the TP53 locus, and the retained TP53 allele is mutated in the majority of cases. 

 The absence of wild type p53 is therefore the most common abnormal finding in astrocytomas malignancy grade II,  resulting in a non-functional p53 pathway. A small percentage of tumours have mutations of one allele but retain one wild type allele. As the p53 protein is believed to function as a tetramer and as tetramers with one abnormal p53 protein may not function normally, the finding of these single mutated alleles together with a wild type allele may well be significant. 

Other genes coding for components of the p53 pathway (fig 5), MDM2 and p14ARF, have been studied in small numbers of these tumours and no abnormalities have been reported. Recent studies of the TP53 related gene, P73, have not identified any mutations.  Other findings considered significant include overexpression of the PDGFRA gene.  Loss of alleles from 6q, 13q, and 22q occur in some astrocytomas. 

There is no evidence to suggest that there is mutation of the single retained tumour suppressor gene RB1 allele at 13q14.2 or the NF2 tumour suppressor gene on 22q.  Deletion mapping of chromosomes 6 shows losses on 6q in a significant number of astrocytomas. 

The potential tumour suppressor genes in all of these regions remain unknown. There are no consistently reported amplified genes or amplified regions of the genome in astrocytomas. The changes found in the astrocytomas form the baseline for progression in the adult diffuse astrocytic tumour series. Epigenetic changes such as hypermethylation of tumour suppressor gene promoters may also play an important role in transcriptional silencing of some of the genes cited above or other important cancer genes and the development of astrocytomas.

Grade III : Medulloblastoma malignancy

The most common chromosomal abnormality in medulloblastomas is iso-chromosome 17q, in which most of the short arm is lost from two chromosomes 17 and they are then fused head-to-head producing a chromosome with two centromers, little 17p and two 17q arms. 

This is observed in 30–50% of cases by using cytogenetic techniques.  These findings have been confirmed by CGH and molecular genetic studies. Many other chromosomal aberrations have been identified using conventional cytogenetic, CGH or molecular genetic techniques—for example, loss of 10q (35%). In addition, several growth and transcription factors have been investigated, some reporting high expression in a subset of tumours for example, erbB2&4.

A major contribution to our understanding of medulloblastoma biology has come from the study of two genetic syndromes exhibiting a predisposition to medulloblastoma formation. Gorlin’s syndrome (hereditary naevoid basal cell carcinoma syndrome) and familial adenomatous polyposis (FAP) syndrome arise from mutations in the PTCH (9q) and APC (5q) genes, respectively, and both are associated with medulloblastoma formation.

The gene products of these two genes take part in two interconnected pathways that are fundamental to neural development and cell turnover. Hemizygous loss and mutations in the retained allele of PTCH in sporadic medulloblastomas have been shown. However, alterations in the PTCH and APC genes as well as other genes coding for components of these two pathways are involved in the development of less than 15% of sporadic medulloblastomas. 

 Other genes involved in the two pathways, including SMO and SUFU,  have been studied and also show loss of wild type in only single, isolated cases. Other genes currently being investigated for their significance in medulloblastoma biology are the myc family  and the PDGF receptors and ligands.

COMMON ADULT TUMOURS

Diffuse astrocytic tumours

 

The adult diffuse astrocytic tumours include the astrocytomas (malignancy grade II), the anaplastic astrocytomas (malignancy grade III), and the glioblastomas (malignancy grade IV). The astrocytoma malignancy grade II tumours have a peak incidence between 25 and 50 years of age, while the glioblastomas have a peak incidence between 45 and 70 years. 

All are more common in males and most are located in the cerebral hemispheres. Glioblastomas are the most common form and are divided into those that develop from a previously diagnosed tumour of lower malignancy grade and those that appear to develop de novo. Both clinical and molecular data support the hypothesis that these tumours may develop from the mutation of different genes but affect the same cellular pathways. 

 The relevance of the histologically based malignancy grading scheme is indicated by patient survival. Patients with an astrocytoma (malignancy grade II) have an average survival of approximately seven years, patients with anaplastic astrocytomas have a median survival half that time,  while glioblastoma patients have an average survival of between 9–11 months. 

 This is despite the best currently available treatments. The astrocytomas (malignancy grade II) and anaplastic astrocytomas have been well documented to progress to tumours of higher malignancy grade. The tumour cells of astrocytomas (malignancy grade II) resemble astrocytes, show little nuclear atypia, and have extensions producing a loosely textured matrix (fig 4). They generally express S-100 protein and glial fibrillary acidic protein.

Anaplastic astrocytomas (malignancy grade III) show increased cellularity but the tumour cells still show histological and immunocytochemical characteristics of astrocytes. The tumour cells are more pleomorphic than found in astrocytomas, show distinct nuclear atypia, and there is mitotic activity.

No evidence of spontaneous tumour necrosis or abnormal microvascular proliferation is permitted in anaplastic astrocytomas. Glioblastomas (malignancy grade IV) are more cellular than the anaplastic astrocytomas. The tumour cells show a wide spectrum of morphologies, can be very pleomorphic with giant forms, but generally retain some of the phenotypical characteristics of astrocytes.

Mitosis, spontaneous tumour necrosis with pseudopalisading of tumour cells, as well as florid endothelial proliferation, are inevitably found in some areas of a well sampled tumour (fig 4). A large central necrotic area with a ring-like zone of contrast enhancement, representing the viable tumour tissue, can often be identified by neuroimaging. 

Grade II : Showing multiple ependymal canals (H&E)

Chromosomal copy number abnormalities detected by classical cytogenetics and CGH include chromosomes 1, 6, 7, 9, 10, 13, 17, 19, and 22. Deletions are most common with losses on chromosome 22 a frequent event in adult spinal ependymomas (over 50%) but infrequent in paediatric ependymomas. 

Gains have been reported for chromosome 7. These findings have been confirmed by molecular genetic data that have identified losses on 6q, 9p, 10, 11q, 13q, 17p and 19q. The genes targeted by these allelic losses and gains are in most cases unknown, with the exception of the loss of both wild-type copies of the neurofibromatosis type 2 (NF2) gene in sporadic intramedullary spinal ependymomas but not in intracranial ependymomas. Single cases have been reported with loss of other wild type genes such as the MEN1 gene. Germ line mutations of TP53 are uncommon in contrast to the situation in the diffuse astrocytic tumours.

Medulloblastoma

 

Medulloblastoma has a peak incidence in childhood but also can occur into late middle age. Histologically childhood and adult medulloblastoma are identical, being highly cellular, malignant invasive tumours corresponding to WHO malignancy grade IV. 

Medulloblastomas occur in the posterior fossa. They consist of densely packed tumour cells with round to oval or carrot shaped hyperchromatic nuclei with scanty cytoplasm, high mitotic and apoptotic rates, and usually neuroblastic rosettes in some areas (fig 3).

Neuronal differentiation and glial differentiation may be present. Microvascular proliferation is relatively uncommon. Tumours arise with similar frequency in the cerebellar vermis (mainly in children) and the cerebellar hemispheres (older patients), and often invade the fourth ventricle, with occasional brainstem involvement.

There is a high risk of seeding through the subarachnoid space due to the tendency of the tumour to penetrate the ependymal surface. Many antigens have been identified focally in medulloblastomas (nestin, vimentin, neurofilament proteins, GFAP, retinal S-antigen, N-CAMs, Trk-A, -B, -C etc). 

However, most are not of any great importance in the day-to-day diagnosis of these tumours. It is most important to differentiate medulloblastomas from atypical teratoid/rhabdoid tumours, as the latter have a very poor prognosis and do not respond to the current relatively successful treatment protocols for medulloblastomas.  In adults the possibility of a metastasis of a small cell lung cancer must often be excluded.

Grade I : Familial syndromes associated with human brain tumours

COMMON CHILDHOOD TUMOURS

Pilocytic astrocytomas

 

Pilocytic astrocytomas most commonly occur in the cerebellum of children. However, they may occur anywhere from the optic nerve to the medulla oblongata. Patients with pilocytic astrocytomas that can be excised have a good prognosis. 

There is an increased incidence of pilocytic astrocytomas in NF1 patients, particularly involving the optic nerve, and these tumours in NF1 patients behave in a particularly benign fashion. Pilocytic astrocytomas are generally biologically non-aggressive and are remarkable among astrocytic tumours in maintaining their grade I status over years and even decades (in contrast to the diffuse astrocytic tumours in adults). 

However, very occasional cases may prove more sinister and progress to more malignant tumours. Pilocytic astrocytomas show a wide spectrum of morphologies, from the pilocytic, bipolar cellular areas with Rosenthal fibres (fig 1) to less cellular protoplasmic astrocytoma-like areas with eosinophilic granular bodies and clear cells. 

The latter are reminiscent of oligodendroglioma and in the posterior fossa can also be confused with clear cell ependymoma. The presence of features typically associated with a malignant biological behaviour (for example, vascular proliferation or mitosis) does not carry the same sinister implications as in the other astrocytic tumours. 

This morphological spectrum can make histopathological diagnosis extremely difficult particularly in the absence of the clinical data that must be provided to the pathologist as outlined above. 

Figure 1 Pilocytic astrocytoma malignancy grade I (H&E). Note the piloid bipolar cells and Rosenthal fibres (arrows). This shows the classical morphology that is generally found somewhere in a pilocytic astrocytoma; other areas can show very different histological patterns

More than 100 cases of pilocytic astrocytomas have been analysed cytogenetically and many more by comparative genomic hybridisation. No consistent findings have been made. The majority show normal cytogenetic and comparative genomic hybridisation (CGH) findings. 

 Adult pilocytic astrocytomas have been found to show the most frequent but again variable abnormalities. Molecular genetic studies have been few and have shown allelic losses on both 17p and 17q including the TP53 and NF1 loci. Few TP53 mutations have been reported and no mutations of the NF1 locus have been reported in sporadic tumours. 

 Recently studies of methylation of the promoter regions of a number of genes reported to be hypermethylated in the adult diffuse astrocytic gliomas have provided somewhat inconsistent data on methylation in pilocytic astrocytomas.

Ependymoma

 

Ependymomas arise at or close to ependymal surfaces and may occur anywhere in the ventricular system as well as in the spinal cord and very occasionally at extraneural sites. The most common location is in the fourth ventricle, followed by the spinal canal, lateral ventricles, and the third ventricle. 

Children have the highest incidence of ependymomas, but they can occur into late middle age. Ependymomas are the most frequent glioma of the spinal cord and this location is common in adults. There are a number of subtypes. 

The least biologically aggressive are malignancy graded as grade 1, and consist of the subependymoma (intraventricular and often symptomless) and myxopapillary ependymoma that most commonly occurs at the cauda equina.

The tumour named ependymoma is malignancy graded as grade II and has a number of histopathological variants. Ependymomas show in some area(s) evidence of an ependymal cell phenotype—by the formation of ependymal rosettes and sometimes canals (fig 2). More commonly perivascular pseudo-rosettes are identified but are not specific for ependymomas. 

Ependymomas (malignancy grade II) are differentiated from anaplastic ependymomas (malignancy grade III) on the basis of low mitotic rate and a low level of nuclear polymorphism, but the borderline between these remains ill defined. Necrosis and microvascular proliferation do not have the same significance in this tumour type as in the adult astrocytic tumours. 

Most ependymomas (malignancy grade II) show immunoreactivity for glial fibrillary acidic protein (GFAP), S-100 protein, and epithelial membrane antigen (EMA).

Glioblastoma Multiforme: Symptoms, Diagnosis & Treatment

Glioblastoma multiforme is considered to be the most common and most aggressive type of primary brain tumor in humans. It is the most malignant form of astrocytomas. An astrocytoma is a glioma that develops from star-shaped glial cells (astrocytes), which are cells that help nerve cells work. 

A glioblastoma multiforme is categorized as a grade IV astrocytoma. This condition can develop unexpectedly. It can develop less commonly from a lower grade, less malignant (cancerous) brain tumor. Most cases are sited in the cerebral hemisphere; however the cancer can also start in the spinal cord or brain stem.

In short term, glioblastoma multiforme is referred to as GBM or glioblastoma. It is one of the most common of all brain tumors that are part of brain cancer. These brain tumors are known to affect all age groups. However, these tumors seem to be most widespread in those people who have age more than fifty years of age. In this article, you will find valuable information pertaining to this glioblastoma multiforme. If you suspect any symptoms of this serious condition, consult your doctor immediately as early treatment leads to a more favorable outcome.

Characteristics of Glioblastoma multiforme:

• More common in men than women
• Common among men and women in their 50s-70s
• Accounts for 23 percent of all primary brain tumors
• Most invasive type of glial tumor
• Grows rapidly
• Commonly spreads to nearby tissue
• May have evolved from a low-grade astrocytoma or an oligodendroglioma
• May be composed of several different kinds of cells (i.e., astrocytes, oligodendrocytes)
  

  Causes of Glioblastoma multiforme:

  Chromosome defects and specific gene mutations may be the cause of glioblastoma as they lead to uncontrolled growth of certain brain cells. Chromosomal changes can also be caused by some environmental factors such as chemicals and radiation, in addition to as yet unidentified carcinogenic agents.
•  Inherited gene mutations are also account for a small percentage of glioblastomas. Yet, no connections have been found between glioblastoma and smoking, diet, cellular phones, or electromagnetic fields. Some proof for a viral cause has been discovered, possibly SV40 or cytomegalovirus.  Some also consider that there may be a connection between polyvinyl chloride (which is commonly used in construction) and glioblastoma. There is a relationship of brain tumor occurrence and malaria, suggesting that the anopheles mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma.
•  
• Other risk factors are:
  
  
• Age: over 50 years old
• Sex: male (slightly more common in men than women)
• Ethnicity: Caucasians, Latinos, Asians
• A low-grade astrocytoma (brain tumor), which often, given enough time, develops into a higher-grade tumor
• One of the following genetic disorders is linked with an increased occurrence of gliomas: Neurofibromatosis, Tuberous sclerosis, Von Hippel-Lindau disease, Li-Fraumeni syndrome, Turcot syndrome

Symptoms of Glioblastoma multiforme:

• Visual loss
• Headache
• Paralysis or sensory loss
• Impaired speech
• Personality change
• Increased pressure inside skull
• Headache frontal lobe tumor
• Vomiting frontal lobe tumor
• Intellectual disability frontal lobe tumor
• Personality changes frontal lobe tumor
• Impaired memory frontal lobe tumor
• Seizures parietal and frontal lobe tumor
• Spatial disorientation parietal lobe tumor
• Loss of positional awareness of body parts parietal lobe tumor
• Poor coordination temporal lobe tumor
• Motor disturbance temporal lobe tumor
• Paresthesia parietal lobe tumor
• Sensory changes parietal lobe tumor
• Lack of emotion frontal lobe tumor
• Convulsions frontal lobe tumor
• Paralysis on one side of body
• Reduced ability to interpret language temporal lobe tumor
• Agraphia parietal lobe tumor
•  

Diagnosis of Glioblastoma Multiforme Tumors:

To diagnose a glioblastoma multiforme tumor, many diagnostic tools are used. If patient suffers from any form of mental dysfunction, then it is typical to a neurologist for a complete examination. Additionally, if a patient is identified to be suffering from headaches, starts experiencing seizures, or if there is any doubt about existence of any degree of inflammation around the brain, then the patient will be sent for a neurological examination to verify whether or not he/she is suffering from brain cancer. In addition to this, following diagnostic tools are used to evaluate a patient.

• Vision Exams
• Hearing Exams
• Brain Fluid Exam
• Computed Tomography
• General Physical
• An X-Ray
• Cerebral Angiography
• Magnetic Resonance Imaging Scan

If you are suffering from the symptoms of a glioblastoma multiforme tumor, it is essential to make sure that you make an appointment with a medical professional as soon as possible. It is truth that this is a serious form of brain cancer and at this stage some treatments are available that may prove to be productive to stopping or slowing the overall progression of the illness.

Glioblastoma Multiforme Treatment:

Glioblastoma multiforme treatment depends on the nature of the tumor, how rapidly it is growing, and what symptoms it causing and where it is located. Radiation therapy, chemotherapy, and surgery can prolong a patient’s life who suffers from this disease.

Chemotherapy:

Chemotherapy is the course of drugs which have been shown to increase life expectancy in about a quarter of Glioblastoma multiforme patients. Life expectancy can be increased anywhere from a few months to up to a year.

Radiation Therapy:

In this therapy, radiations are used to decrease the size of a tumor or eliminate it. Main focus of the treatment is doses of radiation. But, the tumor often resurges within a year and worsens brain tissue further.

Drugs:

Some drugs like anti-convulsants and corticosteroids may be administered to improve the patient’s quality of life. Anti-convulsants drugs are given to minimize epileptic seizures and corticosteroids are given to help the overall function of the body.

Brachytherapy:

In brachytherapy, high doses of radiation are injected into the affected area. It is a rarely used method. But, up to 40 percent of patients need surgery to eliminate tissue damaged by the brachytherapy.

Surgery:

By surgery, the affected tissues are eliminated from the body through biopsy. A tumor can not be eliminated from the body but it helps in evaluating the situation for the patient.

Brain cancer

Brain cancer (tumour) is the abnormal growth of cells in the brain.  As this growth of cells expands it can put pressure on the brain thus with the potential to affect normal functions.  A person with a brain tumour may experience headache, dizziness, seizures, vision problems and muscle weakness.  The good news is that not all brain tumours are malignant – about half of all brain cancers are benign.

In contrast to malignant brain cancer, benign brain cancers do not spread to other parts of the body and grow more slowly.  Benign tumours can still be dangerous if they grow on important parts of the brain and nerves, but they can normally be treated quite successfully.

Malignant tumours on the other hand, grow faster and can spread to other parts of the body.  However, it is rare for a malignant brain tumour to spread to organs outside of the central nervous system, which primarily consists of the brain and the spinal cord.

There are many different cells that make up the central nervous system, and because of this there are different types and subtypes of brain cancers.  There are more than 40 major types of brain tumours. About 80% of brain tumours are known as gliomas, which are made up of glial cells.  Glial cells are the building blocks of connective and supportive tissue in the central nervous system.  

There are different subtypes of gliomas, the most common ones are:

• Astrocytoma, is subtype of glioma which accounts for 60% of all malignant brain tumours.  Astrocytomas are made up of astrocytes (star shaped glial cells).
• Ependymoma, mainly form on the lower part of the brain and the central canal of the spinal cord.  They are the most common type of brain tumour in children.

In addition to gliomas, Meningioma is another type of brain tumour, it affects the membrane that surrounds the brain and spinal cord.  In 90% of cases, meningiomas are benign and they account for 25% of all benign brain tumours.  Meningioma tend to affect women more than men.

Brain cancer is not that common. It accounts for 2% of all cancers with more than 1400 new cases each year in Australia.  With more than 1000 brain tumour-related deaths each year, the average survival rate is less than 30%, however this number can vary greatly depending on the type of brain cancer involved.  The risk of being diagnosed by age 85 is 1 in 109 for men and 1 in 156 for women.

What causes brain cancer disease

None of the known causes of brain Cancer disease. Has been conducting extensive research to identify the cause of preventing cancer occurs. Although there is much more conclusive evidence of a cause of brain tumors, all doctors know that brain cancer is not contagious and does not occur due to head trauma. There have been cases where the cancer has spread to the brain from other parts of the body. (Lung cancer, breast cancer, liver cancer, etc..) Brain cancer can occur at any age. Studies have shown that two groups are affected in old age. From 3 to 12 years and between 40 and 70 are the age groups, in which brain cancer. Because the researchers were able to collect these data has led to the discovery of certain risk factors

Risk of brain cancer was detected through the use of mobile phones

This has been a controversy for some time about the health risks that the phone is for the people, through its use. Although many of the majority of studies have claimed to be conclusive, this study has been done recently, they have shown and increased risk of cancer was detected through the use of mobile phones needs. Located in Stockholm, Sweden, a recent study by the Karolinska Institute was no increased risk of brain tumors in the brain through the use of regular cell phone. This study involved 634 people over a period of two years. In all 209 patients who had brain tumors and 425 were in perfect health. 

How to know symtoms of brain cancer

Brain cancer for about 1.4% of all cancers and about 2.4% of all cancer deaths. This may not seem like much, but do not be fooled, the numbers of the severity of brain tumors. When the cancer is malignant tumors grow aggressively and overwhelm healthy cells take their place, the blood and nutrients. This is an area of great importance, because the brain is the most important part of your body and controls everything. Whenever there is something wrong with the brain affects the entire body. Know the symptoms of brain cancer and are able to recognize these symptoms, very important for our survival and prognosis of this deadly diseasre.

How to determine brain cancer

The most likely reason for the request for information on how to determine brain cancer in us, you may be experiencing symptoms of the impression (but hopefully) not caused by brain tumors. There are many questions that this series to continue and is the result of research on various aspects of the problem of brain tumors, including treatment and outcome. Research shows that there are areas of agreement and points of disagreement between those who offer help and advice. In addition, there are conflicting reports of patients suffering from brain cancer patients and their families about the value and effectiveness of diagnostic and therapeutic options.

Symptoms of Brain Cancer

Do you know symptoms of brain cancer? Read this article for knowledge about it. Brain cancer is a disease of the brain where cancer cells (malignant) grow in the brain tissue. Tumors composed of cancer cells are called malignant tumors, and those composed of noncancerous cells are called benign tumors.

Cancer cells that develop from brain tissue are called primary brain tumors. Primary brain cancer starts in the brain. Brain tumors can be benign, with no cancer cells, or malignant, with cancer cells that grow quickly.

Metastatic brain tumors are made of cancerous cells from a tumor elsewhere in the body. Symptoms of Brain Cancer is Brain tumors can damage vital neurological pathways and invade and compress brain tissue.

 

Brain tumors can often present different symptoms depending on the location of the tumor. Fits are one of the commonest symptoms of brain cancer. Seizures are a common symptom of benign brain tumors and slow-growing cancers. If someone notices any of these symptoms persisting, they should contact a doctor and are tested for any potential problems.

 Constant headaches and weakness may be a sign of an issue pertaining to the brain. There are also symptoms that are more vague and that people may not immediately associate with brain cancer. Some of the nonspecific physical Symptoms of Brain Cancer include abnormalities in vision and difficulty with speech as well as unexplained, persistent vomiting that tends to occur in the morning

How to Treat Brain Cancer

The brain is a soft, spongy mass of tissue. It is protected by the bones of the skull and three thin membranes called meninges. Watery fluid called cerebrospinal fluid cushions the brain. This fluid flows through spaces between the meninges and through spaces within the brain called ventricles.

Brain tumors that result from this transformation and abnormal growth of brain cells are called primary brain tumors because they originate in the brain. The purposes of surgery are to confirm that the abnormality seen on the brain scan is indeed a tumor and to remove the tumor. If the tumor cannot be removed, the surgeon will take a sample of the tumor to identify its type. In some cases, mostly in benign tumors, symptoms can be completely cured by surgical removal of the tumor. Your neurosurgeon will attempt to remove the tumor when possible.

Gliadel wafers are implanted into the cavity left in the brain after surgical removal of the brain tumor.  The wafers deliver the active drug carmustine directly to the affected area of the brain.     Depending on the size of the cavity, 7 to 8 wafers are implanted.  Each wafer is 1.45 cm in diameter, 1mm thick and contains 7.7 milligrams of carmustine — resulting in a 61.6 mg dose when eight wafers are implanted. 

 

Neurologists and other brain tumor treatment team member’s work together to determine the treatment approach that best meets the each individual’s needs. Because new treatments continually develop, several options may be available for patients at different points in their treatment. The pros and cons of each option are discussed in detail during treatment planning. The treatment plan may include surgery, radiation therapy, and chemotherapy.

 

 

 Doctors must balance removing as much of the tumor as possible without harming healthy brain tissue. In many cases, the patient is brought back to consciousness while vital areas, such as those controlling speech, are worked on, according to medical experts.

 Malignant brain cancer is one of the most lethal types of cancer in adults and is the second leading cause of cancer death in children. Many current ways of treating the disease fail to provide long-term management because they ineffectively target tumor cells and harm the health and vitality of normal brain cells.

The three major types of conventional brain cancer treatment are surgery, radiation therapy and chemotherapy. In brain cancer treatment surgery if the neurosurgeon cannot remove the tumor, they will still take a biopsy and examine it to decide on other brain cancer treatment options. Moreover, patients who undergo brain cancer treatment at Cancer Treatment Centers of America work closely with a team of our cancer experts to determine the appropriate brain cancer treatment plan.