Astrocytic neoplasms

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Astrocytic neoplasms

Glial neoplasms (gliomas), as a group, are the most common CNS neoplasms. The classification of gliomas is based on histologic similarities to glial cell types, including astrocyte and oligodendrocyte.

DIFFUSE ASTROCYTIC NEOPLASMS – ASTROCYTOMA, ANAPLASTIC ASTROCYTOMA, GLIOBLASTOMA

Astrocytoma, anaplastic astrocytoma, and glioblastoma constitute a range of diffusely infiltrating astrocytic neoplasms, which occur throughout the CNS. They are referred to as ‘diffuse astrocytic tumors’ to distinguish them from the pilocytic astrocytoma and other rarer forms of localized or circumscribed astrocytic neoplasms (e.g. pleomorphic xanthoastrocytoma and subependymal giant cell astrocytoma). The diffuse astrocytic neoplasms are commonest in the cerebrum in adults and brain stem in children. They are relatively uncommon in the cerebellum and spinal cord. The glioblastoma has the highest incidence of any primary neuroepithelial neoplasm, accounting for approximately 50% of intracranial gliomas.

GENETICS, MALIGNANT PROGRESSION, AND GRADING OF ASTROCYTIC NEOPLASMS

One important characteristic of the astrocytoma is its propensity for anaplastic transformation; 50–75% (in different series) of diffuse astrocytomas progress to anaplastic astrocytomas or, ultimately, glioblastomas. Time to anaplastic transformation is highly variable, often 3–5 years but occasionally 10 years. Neoplastic progression is associated with the sequential acquisition of multiple genetic abnormalities (Fig. 35.1). The origin of astrocytic neoplasms may include neural stem cells, progenitor cells, or differentiated glial cells. Isocitrate dehydrogenase (IDH1, IDH2) and TP53 gene mutations are considered to be early events in neoplastic progression. In contrast, allelic loss on chromosome 10 occurs predominantly in glioblastomas. Molecular genetic studies have revealed differences between glioblastomas that evolve over years from low grade astrocytomas (secondary) and those that arise de novo (primary) (Table 35.1, Fig. 35.2). In particular, EGFR overexpression is common in primary glioblastoma, while IDH1 mutations are common in secondary glioblastoma. The vast majority of glioblastomas are primary or de novo, rather than secondary in nature. Radiologic images may provide clues to the grade and type of astrocytic neoplasm (Fig. 35.3). Evidence from comprehensive analyses of molecular genetic abnormalities in primary glioblastomas suggests that a defect in at least one of three pathways controlling cell proliferation, survival, and apoptosis is crucial and common to their tumorigenesis (Fig. 35.4), but a majority of these primary glioblastomas show aberrations in all three pathways. More recently, there has been a growing understanding of epigenetic changes that modulate gene expression, but do not alter the DNA sequence itself, and how they can also affect tumor prognosis and response to therapy (Fig. 35.5). In addition, ongoing work suggests that global assessments of RNA transcription patterns can further sub-classify glioblastomas into prognostically significant groups that will likely be important for development of molecular-guided therapies (Table 35.2).

Table 35.1

Genetic characteristics of primary and secondary glioblastoma (GBM)

	Primary GBM	Secondary GBM
EGFR overexpression	>60%	<10%
MDM2 overexpression	>50%	<10%
PTEN gene mutation	>30%	<10%
TP53 gene mutation present	<10%	>60%
Loss of chromosome 19q	<10%	>50%
RB1 promoter hypermethylation	<15%	>40%
IDH1/IDH2 mutation	<4%	>80%

Table 35.2

Glioblastoma molecular sub-classification by gene expression (RNA transcript) profiles

CHI3L1, chitinase 3-like 1; EGFR, epidermal growth factor receptor; IDH, isocitrate dehydrogenase; MET, met proto-oncogene; NES, nestin; NFκBIA, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; NF1, neurofibromin 1; OLIG2, oligodendrocyte lineage transcription factor 2; PDGFRA, platelet-derived growth factor, alpha polypeptide.

35.1 Acquisition of common genetic abnormalities through the range of diffuse astrocytic neoplasms.
IDH, isocitrate dehydrogenase; PDGFRA, platelet-derived growth factor, receptor A alpha polypeptide; RB1, retinoblastoma 1.

35.2 Genetic pathways to formation of gliomas.
Primary and secondary glioblastomas have different genetic pathways. Pilocytic astrocytomas are genetically distinct from the infiltrating astrocytomas. Oligodendrogliomas share the IDH1 mutation with other low grade astrocytomas but are distinguished by a high frequency of the chromosomes 1p/19q translocation. Chr, chromosome.

35.3 Common radiologic presentations of glial neoplasms.
(a) A low grade astrocytoma (WHO grade II) or other low grade infiltrating glioma often presents as a non-enhancing ill-defined lesion. A minority of non-enhancing tumors may be anaplastic in nature. (b) An enhancing, poorly defined glial neoplasm is most often an anaplastic astrocytoma, other anaplastic glioma, or glioblastoma. (c) A ring-enhancing lesion should prompt strong consideration for a glioblastoma. Abscesses and high grade non-glial malignancies can produce a similar pattern. (d) Astrocytic neoplasms not infrequently enter or cross the corpus callosum sometimes creating a ‘butterfly glioma’ pattern. (e) A cystic mass with an enhancing mural nodule is typical of ganglioglioma and pleomorphic xanthoastrocytoma (often in the temporal lobe) and of hemangioblastoma or pilocytic astrocytoma (often in the cerebellum). (f) While multicentric lesions may reflect metastases, lymphoma, or non-neoplastic lesions, gliomas occasionally can be multifocal as in this example. (g) Diffuse involvement of large areas rather than a distinct mass suggests gliomatosis cerebri. (h) While a solidly enhancing nodular mass may be seen with glioblastoma, a variety of low grade and high grade lesions may show this relatively non-specific pattern. Malignant lymphoma, as in this case, metastatic malignancies, pilocytic astrocytoma, and ganglioglioma may be solidly enhancing and circumscribed as well. (Courtesy of Dr A Lai, UCLA Medical Center, USA.)

35.4 Three signaling pathways are commonly aberrant in primary glioblastomas.

35.5 Promoter methylation of O6-methylguanine-DNA methyltransferase (MGMT).
(a) Promoter methylation shuts down gene expression of MGMT which is important for DNA repair. (b) Transfer of an alkyl group (CH₃) from the O6 position of methylguanine to a cysteine residue on the MGMT protein ‘uses up’ the protein – hence the appellation, ‘suicide enzyme’. The amounts of MGMT protein within a tumor cell are crucial in repairing DNA damage and allowing the cell to avoid a G:C to A:T transition mutation that could result in deleterious or lethal mutations.

STEM CELLS AND GLIOMAS

Cancer stem cells (CSCs) are enriched in perivascular and perinecrotic/hypoxic ‘niches’ that provide the appropriate microenvironment for maintenance or propagation.

CSCs are chemoresistant and radioresistant, providing a nidus for tumor regrowth.

CSCs can also drive angiogenesis, invasion, and metastasis.

Adult neural stem cells have an unlimited ability to self-renew while remaining pluripotential, i.e. able to differentiate into many cell types.

Stem cells give rise to progenitor cells that have limited self-renewal capabilities and restricted ability to differentiate into different cell types.

Neural stem cells are located in the subventricular zone and dentate gyrus.

Gliomas may arise from neural stem cells or progenitor cells.

Genetic and epigenetic changes result in glioma formation and progression.

Once a tumor is established, a small subset of tumor cells retain or gain stem cell-like properties and have been given various names, including cancer stem cells or brain tumor stem-like cells.

Historically, several grading systems have been applied to diffuse astrocytic neoplasms (Table 35.3). These use histologic parameters to separate the range of astrocytic neoplasms into three or four tiers, providing some indication of biologic behavior. Although there are some differences in the applied parameters, there is a broad correspondence between the systems and WHO nomenclature. Use of the WHO nomenclature is preferred (Table 35.4), because ambiguity may occur when the grading system is not specified; for example, the term ‘grade 2’ has different implications for treatment and prognosis in the WHO and Kernohan systems. In addition, there is no evidence to suggest that other grading systems offer any advantage over WHO nomenclature. Various clinical, pathologic, and genetic variables, including histopathologic diagnosis, are prognostic indicators in astrocytic neoplasms (Table 35.5).

Table 35.3

Comparison of grading systems

^a Grade 1 neoplasms are pilocytic astrocytomas.

^b Grade 1 neoplasms include pilocytic astrocytomas.

^c Grade 1 neoplasms are very rare.

^d Astrocytoma with focal anaplasia.

Table 35.4

WHO grading for diffuse astrocytomas

Astrocytoma WHO grade II	Atypia but no mitoses^a
Anaplastic astrocytoma WHO grade III	Atypia and mitoses
Glioblastoma WHO grade IV	Atypia, mitoses, vascular proliferation^b and/or necrosis

^a A rare mitosis in an otherwise typical low grade astrocytoma does not require elevation to grade III.

^b Vascular proliferation is defined as ‘endothelial’ proliferation 2 cell layers or more. The term ‘endothelial’ is used loosely as smooth muscle markers are expressed in the hyperplastic vascular wall. This may mimic glomeruli; so-called ‘glomeruloid’ vascular proliferation.

Table 35.5

Prognostic indicators in diffuse astrocytic neoplasms

Age (young age – favorable)

Karnofsky performance score (high score – favorable)

Macroscopic surgical resection (gross resection – favorable)

Histological grade (low WHO grade – favorable)

MGMT methylation status (presence – favorable)

IDH1/IDH2 mutation status (presence – favorable)

Proneural gene expression profile (presence – favorable)

IDH1/IDH2, isocitrate dehydrogenase 1/isocitrate dehydrogenase 2; MGMT, O6-methylguanine DNA methyl transferase.

DIFFUSE ASTROCYTOMAS

Commonly present with epilepsy.

Often produce neurologic deficits and symptoms and signs of raised intracranial pressure at a later stage.

Acquire areas of contrast enhancement on MRI images when undergoing anaplastic progression.

Have a variable prognosis that correlates with a range of clinical factors (Table 35.5).

ISOCITRATE DEHYDROGENASE (IDH) AND GLIOMAS

The vast predominance of mutations affect residue 132 in exon 4 of IDH1.

IDH1 mutation is associated with better prognosis.

IDH1 mutation is not predictive of response to temozolomide or radiotherapy.

Mutation of an homologous IDH2 gene has a similar effect on prognosis.

IDH1/2 mutation is common in astrocytoma, oligodendroglioma, oligoastrocytoma, and their anaplastic counterparts.

IDH1/2 mutation is common in secondary glioblastoma, but rare in primary glioblastoma.

Rare IDH1 mutant primary glioblastomas arise in young adult patients, contain TP53 mutations, and lack EGFR amplification.

IDH1 mutations are heterozygous (only one copy of the gene is mutant) and are gain of function mutations. Wild-type IDH1 catabolizes production of alpha-ketoglutarate and NADPH. In contrast, mutant IDH1 produces R(-)-2-hydroxyglutarate (2HG), a metabolite associated with carcinogenesis.

Patients with L-2 hydroxyglutaric aciduria are prone to developing gliomas.

In vitro studies show that IDH1 mutation is associated with an increase in the levels of hypoxia-inducible factor subunit HIF-1α, a transcription factor that affects numerous genes involved in promoting tumor angiogenesis, proliferation, and migration.

IDH1 mutation is rare in other brain tumors and most systemic cancers, except for acute myeloid leukemia.

O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) METHYLATION

Methylation is an epigenetic phenomenon, in which CpG islands (clusters of CpG dinucleotides) in the promoter region of certain genes are methylated.

With promoter methylation, there is local condensation of chromatin structure preventing binding of transcription factors and shutting down transcription.

Methylation of the MGMT gene, which encodes for a DNA repair enzyme, may increase susceptibility of tumors to mutagenesis (Fig. 35.5).

A glioblastoma with a methylated MGMT status is associated (in some studies) with a better response to temozolomide, a common alkylating agent therapy, than an unmethylated tumor.

In some animal and human studies, low MGMT protein levels, as measured by immunohistochemistry, are similarly associated with response to temozolomide.

The association of MGMT methylation status with outcome may reflect other mechanisms beyond DNA repair.

ASTROCYTOMA

Generally, presenting in the third or fourth decade (Table 35.6), diffuse astrocytomas are divided into fibrillary, protoplasmic, and gemistocytic variants. The fibrillary astrocytoma is encountered most frequently. This variant may contain scattered cells with a gemistocytic phenotype, which by convention (WHO classification) constitute >20% of cells in the gemistocytic astrocytoma. The protoplasmic astrocytoma is very rare; some pathologists believe that it is not a distinct variant, but represents a phenotype present in other gliomas.

Table 35.6

Age at presentation and prognosis of diffuse astrocytic neoplasms

MACROSCOPIC APPEARANCES

Cerebral astrocytomas diffusely expand the white matter, sometimes distorting the overlying gray matter (Fig. 35.6). Radiologically, low grade astrocytomas are generally non-enhancing (Fig. 35.3a). Cortical or subcortical invasion plus associated edema produce expansion of gyri.

35.6 Astrocytoma.
(a) An astrocytoma diffusely invades the cerebrum producing distortion and expansion of normal structures. The neoplasm produces midline shift and is poorly demarcated. (b) CT scan. A poorly defined mass in the right frontal lobe has lower density than the surrounding cerebrum and has produced midline shift. (Courtesy of Dr J S Millar, Wessex Neurological Center, UK.)

The neoplastic process is poorly demarcated; an abnormal texture and slight discoloration of the white matter may be the only clues to its presence. Some neoplasms are gelatinous or tough and therefore more obvious. Macroscopic cyst formation can occur. Cysts in astrocytomas contain clear yellow fluid, in contrast to the slightly turbid fluid in glioblastoma cysts. Astrocytomas of the brain stem and spinal cord expand normal tissues in a fusiform fashion. Brain stem astrocytomas are frequently centered in the pons and an exophytic component may encircle the basilar artery. Spinal cord astrocytomas may be associated with a syrinx.

EPIGENETIC MODIFICATIONS IN GLIOBLASTOMA

Hypermethylation of DNA. Transcription of specific genes is shut down, resulting in loss of protein product and impacting genes and pathways potentially regulating proliferation, apoptosis, migration, and invasion. RB, PTEN, TP53, and CDKN2/Ap16 are examples of tumor suppressor genes that are hypermethylated in some glioblastomas. Hypermethylation of the MGMT promoter is associated with better survival. A particular pattern of methylation called the glioma-CpG island methylator phenotype (G-CIMP) is strongly associated with a proneural gene expression phenotype as well as IDH1 mutation.

Hypomethylation of DNA. Global hypomethylation occurs in many primary glioblastomas (~80%). The effect of hypomethylation may be inappropriate transcriptional activation of genes. Marked global hypomethylation in glioblastoma has been associated with increased cellular proliferation, in part due to activation of oncogenes like MAGEA1. Hypomethylated repetitive sequences are also genetically unstable and are prone to copy number aberrations.

Aberrant histones. Histones are protein components of chromatin that have functions in spooling DNA and regulating gene expression. Anomalous histone H3K9 methylation and decreased H3K9 acetylation may predispose CpG islands to hypermethylation. Mutations of histone deacetylase genes (HDAC2, HDAC9) and histone demethylases (KDM3A, KDM3B), and histone methyltransferases (SETD7, MLL) have been identified in glioblastoma.

MicroRNA (miRNA). Each of these short, non-coding RNAs (19–27 nucleotides) can potentially bind several different messenger RNA (mRNA) sequences, preventing translation or promoting degradation of the respective genes. Different miRNAs are over-expressed or repressed in primary glioblastoma with various effects. Increased levels of miRNA26a repress PTEN and RB, while upregulation of miRNA21 has an antiapoptotic effect. In contrast, over-expression of miRNA-128 can block self–renewal capacity of stem cells in vitro.

GLIOMA-CPG ISLAND METHYLATOR PHENOTYPE (GCIMP)

Specific cancer-related genes are believed to be methylated in a coordinated fashion, in contrast to random or stochastic global methylation.

GCIMP predicts improved prognosis in glioblastoma patients.

GCIMP in glioblastoma is associated with a median age at diagnosis of 36 years compared with 58 years for patients without the phenotype.

GCIMP is common in low- and intermediate-grade diffuse gliomas, secondary glioblastomas, and in tumors that have an IDH1 mutation.

GCIMP is present in over 90% of oligodendrogliomas compared with 45% of astrocytomas.

GCIMP is strongly associated with a ‘proneural’ gene expression profile.

MICROSCOPIC APPEARANCES

By definition, diffuse astrocytomas insidiously invade brain tissue, surrounding normal neurons and glia. This behavior provokes a variable reaction involving astrocytosis and activation of microglia. The cells of some diffuse astrocytomas tend to remain in white matter, avoiding overlying gray matter. Neoplastic cells in some areas are less infiltrative, forming a mass, which may contain microcysts, but necrosis and microvascular proliferation are not features of the diffuse astrocytoma.

Cytologically, neoplastic cells in diffuse astrocytomas show mild atypia, particularly nuclear pleomorphism and hyperchromasia (Fig. 35.7). The cells of fibrillary astrocytomas may appear as bare nuclei, their tenuous fibrillary processes blending with the brain’s parenchyma. Alternatively, they show varying degrees of astrocytic differentiation, exhibiting prominent fibrillary strands of eosinophilic cytoplasm, or a plump cell body in which the nucleus is displaced by homogeneously eosinophilic cytoplasm, the gemistocytic phenotype (Fig. 35.8).