Pathology of Diffuse Astrocytomas

Updated: Nov 04, 2015
Author: Roger E McLendon, MD; Chief Editor: Adekunle M Adesina, MD, PhD 

Definition and Overview

Infiltrative astrocytomas represent a group of astrocytic gliomas that are prone to exhibit diffuse invasion of the brain parenchyma. This subset of gliomas are distinct from other glioma types that exhibit a more circumscribed appearance, and they are most often surrounded by reactive gliosis along their margins. Occasional examples of infiltrative astrocytomas, particularly the highest grade, glioblastoma, may exhibit sharp margins; however, such circumscription represents pseudocapsule-like appearances as may be seen in sarcomas. Other less demarcated margins with infiltration into the surrounding parenchyma are usually obvious.

The majority of infiltrative astrocytomas arise in the cerebrum, but no region of the central nervous system (CNS) is spared as infiltrative gliomas have been described in the basal ganglia, brainstem, cerebellum, and spinal cord. Based on histologic and molecular findings at the time of the original diagnosis, a prognostic grade can be assigned to an infiltrative astrocytoma. Defined histologic types and grades include the well-differentiated astrocytoma, which is formally designated the diffuse astrocytoma by the World Health Organization (WHO) (WHO grade II),[1] whereas the higher grades of the biologic spectrum are assigned as anaplastic astrocytoma (grade III) and glioblastoma (grade IV).

Anaplastic astrocytomas represent the intermediate stage in the spectrum of astrocytic neoplasms that range from diffuse astrocytoma to glioblastoma. Evidence that these tumors have progressed from a lower grade of malignancy is derived from a variety of sources. Epidemiologic data support a peak incidence in the fifth decade, a point between the peak incidence of diffuse astrocytomas (fourth decade) and glioblastomas (seventh decade).[2, 3]

Pathologic confirmation comes from serial biopsies of individuals with previous histories of low-grade astrocytomas. Most recently, molecular data support a direct progression from diffuse astrocytoma to anaplastic astrocytoma to glioblastoma in patients whose tumors bear mutations of the isocitrate dehydrogenase (IDH1) and TP53 genes a finding marking the pathogenic pathway of 5% of all glioblastomas.[4, 5] Biopsy sampling is clearly an issue in the accurate assessment of prognosis in the patient with an astrocytic tumor.

Two studies stated that genetic sequencing may be a better way of characterizing gliomas than classic histopathology. The first study reported that three molecular markers could classify gliomas into five principal groups. The second study concluded that the integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class.[5, 6, 7]  These findings were also reported in a 2013 study.[8]


The diffuse astrocytoma (grade II) is the earliest stage of infiltrating astrocytic tumors. No premalignant stage of this tumor has been recognized. At the time of diagnosis, most of these tumors will exhibit overexpression of the platelet-derived growth factor receptor (PDGF)-alpha, mutation of the IDHI gene, and up to one half will exhibit gene mutation or deregulation of the expression of the TP53 gene.[4] A majority of these tumors will exhibit polysomy of the epidermal growth factor receptor (EGFR) genetic locus on chromosome 7 in subsets of tumor cells.

The anaplastic astrocytoma (grade III) represents an intermediate stage in the progression of diffuse astrocytoma to glioblastomas both histologically and in molecular features. As an intermediate stage of a biologic spectrum, there is some controversy over the histologic landmarks that identify this tumor. This controversy resides at the low and high ends of the scale. Although the WHO grading system suggests the use of a finding of mitotic activity to distinguish between diffuse astrocytoma and anaplastic astrocytoma, it also indicates that the size of the biopsy in which the mitotic counts are found should also be considered.

Given the histologic difficulties in characterizing exactly where along the biologic spectrum that anaplastic astrocytoma begins from diffuse astrocytoma and ends at glioblastoma, it is no surprise that the molecular features of these tumors also reflect a spectrum of changes. However, it has been demonstrated that mutations of IDH1 and TP53 persist in these tumors, and the percentage of cells exhibiting EGFR polysomy also increases as biologic progression proceeds.[4]

Glioblastomas (grade IV) can be divided into at least 2 different types based on their clinical features of progression. 5% of tumors arise in patients with previous lower grade astrocytomas, and their tumors continue to exhibit TP53 and IDH1 mutations, as well as higher percentages of tumor cells with polysomy for the EGFR locus.

In the 95% of glioblastomas that arise de novo, the molecular profile is characterized by EGFR amplification (defined as >5 copies) in up to 40% who also often retain wild-type TP53 and IDH1 genes. These EGFR copy number increases are also often accompanied by loss of the PTEN locus on chromosome 10q23. In up to 40% of cases with EGFR amplification (representing 16% of all glioblastoma multiforme), there is an emergence of a constitutionally active EGFR deletion mutant known as the EGFRvIII, which has a frame-shift mutation resulting in the loss of the extracellular receptor domain and is capable of autophosphorylation of the tyrosine residues in the EGFR intracellular signaling domain.[1]

Diffuse gliomas of childhood represent a special category of diffuse gliomas based on  genotypic changes.  Mutations in IDH1 and co-deletions of 1p,19q are extremely rare in this age group. In contrast, the midline gliomas (including diffuse intrinsic pontine glioma as well as those arising in the thalamus and spine) are prone to exhibit mutations in H3F3a gene affecting K27 exon while the non-brainstem gliomas exhibit mutations in H3F3A affecting either K27 or G34 exons, the latter of which are also accompanied by mutations in ATRX.[9, 10]


Glioblastomas represent the most common and the most deadly of the primary brain tumors. In the United States, the incidence is 5 new cases per 100,000 with a bimodal distribution affecting young children and older adults, with a low incidence among teenagers and young adults. Mean survival is less than 1 year[11] and only approximately 20% of patients survive up to 2 years. Poorer prognosis is associated with older age and low clinical performance score at diagnosis. There is a slight male predominance and a modest racial predominance in white individuals.[2, 3] Glioblastomas can be found in association with Li-Fraumeni syndrome and Lynch syndrome.[1]


The incidence of well-differentiated astrocytomas in the United States is stated to be 0.10; that of anaplastic astrocytomas is 0.47; and that of glioblastomas is 3.05.[2, 3] Among all diffuse astrocytomas, there is a two-fold higher predominance in white individuals (0.45) compared with black individuals (0.20).[2, 3] Among anaplastic astrocytomas and glioblastomas, there is a moderate male-to-female predominance of approximately 1.6:1.[2, 3]

The tumors arise in all age groups. Infantile tumors suggest the possibility of intrauterine origin as congenital glioblastoma. Among anaplastic astrocytomas and glioblastomas, a biphasic incidence curve is noted with a small peak in the first decade, a nadir in the second and early third decade, and a gradual increase through the fourth and fifth decades to a peak in the sixth decade.[2, 3] In this overall scheme, it is noted that grade II tumors peak in the fourth decade, anaplastic astrocytomas peak in the fifth decade, and glioblastomas account for the vast majority of the tumors in the sixth decade and peak in the seventh to eight decades.[2, 3]


Clinical Features

Clinical symptoms of diffuse astrocytomas are the result of brain irritation (eg, seizures), increased intracranial mass (eg, headaches), or brain invasion (eg, hemiparesis, dysphasia). Tumoral progression from lower to higher grades is associated with a concomitant lower incidence of seizures and a higher incidence of focal neurologic deficits.

Tumors originating in clinically silent areas of the brain may be quite extensive at diagnosis but present with only signs of raised intracranial pressure, including headaches, nausea, diplopia, personality changes, and lethargy.[12] Inheritable brain tumor syndromes that have an association with a propensity to form astrocytomas includes Li-Fraumeni Syndrome (TP53 mutation syndrome), Turcot-Lynch syndrome (DNA mismatch repair loss), and neurofibromatosis type 1. Rare familial astrocytomas clusters have also been described.[13]

There are no specific laboratory studies that are helpful in making a specific diagnosis of anaplastic astrocytoma.


Imaging Studies

Radiographic clues to the presence of a diffuse astrocytoma would include asymmetry and/or enlargement of a region of the brain, abnormal computed tomography (CT) scan density and magnetic resonance imaging (MRI) signal abnormality, particularly T2-weighted images; however, neither the T2-signal abnormality nor enhancement is a good indicator of the extent of the astrocytoma; the tumor may extend beyond the apparent imaging abnormality.[14]

The imaging findings of anaplastic astrocytoma are heterogeneous, as expected of a tumor that lies in the biologic spectrum between a low-grade, relatively indolent tumor and a high-grade, aggressive tumor. The diffuse astrocytoma is characterized on MRI by a lack of enhancement with gadolinium and a bright signal on T2-weighted images, whereas the glioblastomas are characterized by bright ringlike enhancement associated with regions of tumoral necrosis.

The anaplastic astrocytoma is represented by images that bridge the spectrum. On unenhanced CT scans, the mass is often hypodense but may have areas of relatively normal density with indiscrete borders. However, low-density cystic areas, high-density hemorrhage, and calcifications are infrequent. In contrast to the diffuse astrocytoma, malignant progression may be noted by hypodensity on T1-weighted MRIs and hyperintensity on T2-weighted images. Some degree of contrast enhancement is expected and is frequently heterogeneous and irregular.[12]

In contrast, glioblastomas exhibit very heterogeneous signaling characteristics indicative of regions of infiltration, high cellular density, tumoral breakdown, vascular leakage, and hemorrhage. The mass usually has heterogeneous T1 signal intensity: low signal – intensity areas represent tumor or edema; areas of higher signal may reflect subacute hemorrhage or proteinaceous material; areas of low signal intensity may reflect acute or old hemorrhage.

The signal intensity on T2-weighted imaging is also heterogeneous; areas of increased signal reflect vasogenic edema, and well-defined high signal areas may represent areas of cyst formation or cystic necrosis. The T2 signal may also be diffuse, ill-defined, and subtle in the case of more infiltrative tumors. Contrast enhancement is variable; a thick shaggy rim of enhancement is often present (as seen in the image below), with enhancing septations or cysts present. The extent of enhancement by no means defines the extent of the tumors; nonenhancing tumors may extend well beyond the confines of the enhancing portion.[15]

Contrast-enhanced T1-weighted magnetic resonance i Contrast-enhanced T1-weighted magnetic resonance image exhibiting a shaggy ring of enhancement in a glioblastoma.

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Medscape Reference topic Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.


Gross Appearance

The diffuse astrocytomas, as their name implies, distribute evenly throughout the white matter, and are most commonly initially located in the frontal or temporal lobe. The affected lobe demonstrates a loss of the normal gray-white junction, with the central region being ivory white and generally firmer than normal brain and occasionally associated with small cysts in the white matter. In contrast to higher grade examples, a grade II tumor has a modest blood supply, which usually appears to be less vascular than the adjacent brain.

The gross appearance of an anaplastic astrocytoma is highly variable, ranging from the appearances of the lower grade tumor described above to a softer, gray, and only modestly vascular tumor. Typically, both lower grade and higher grade regions are encountered, representative of the tumor's biologic progression from the lower grade precursor. Furthermore, regions with a gray purple appearance and having a rich blood supply may also be encountered, suggesting progression to a glioblastoma (see the following image).

Axial section of a brain exhibiting a frontal lobe Axial section of a brain exhibiting a frontal lobe tumor with a focus of hemorrhage and surrounding discoloration that are indicative of a high-grade infiltrating astrocytoma that is in the process of progressing to glioblastoma.

The gross appearances of glioblastomas are also highly variable. Necrosis associated with purplish blood vessels and brown hemosiderin deposition is indicative of progression to grade IV, as seen in the following image.

Gross photograph of a glioblastoma with diffuse he Gross photograph of a glioblastoma with diffuse hemosiderin staining of the white matter, enlargement of the corpus callosum, and tumor evident in the contralateral hemisphere.

Occasionally, the tumor may be the same color as normal white matter and is only differentiated from the surrounding brain by its soft consistency and thromboses or serpiginous blood vessels. Tumors near the midline tend to cross the corpus callosum and present with bilateral hemispheric disease. Tumors adjacent to the ventricles tend to grow along the ependymal surface.

In up to 5% of cases, multifocal disease is evident at the time of diagnosis (see the image below). Although most tumors involve one lobe at the time of presentation, 10% or more will present with gliomatosis cerebri with involvement of multiple lobes The visible mass of the tumor may be a predominantly necrotic tissue surrounded by a thin rim of viable cells or a purple island of very vascular soft tissue. Foci of hemorrhage are not uncommon.

A whole-mount histologic section of a brain staine A whole-mount histologic section of a brain stained by Luxol Fast Blue (LFB) stain shows multiple foci of pale glioblastoma tumor cell clusters in a background of diffusely infiltrative glioblastoma (LFB, 1× original magnification).

Histologic Findings

Diffuse astrocytomas, in the majority of examples, have a characteristic appearance of increased cellular density associated with modest nuclear pleomorphism, increased intercellular edema, and occasional bubbly collections of fluid known as "microcysts" (see the following image).

Diffuse astrocytoma characterized by modest hyperc Diffuse astrocytoma characterized by modest hypercellularity, nuclear pleomorphism, and numerous small microcysts (hematoxylin & eosin, 20× original magnification).

Freezing tissue for intraoperative analysis can induce changes in the histology that renders the edema and microcystic change unidentifiable. Therefore, a preservation of an unfrozen piece of tissue is recommended. In large resections (sections greater than 1 x 1 cm), the cellular density is uniform with little variation between gray and white matter. In most circumstances, the tumor cells infiltrate the gray matter without accumulating (satelliting) about neurons or blood vessels. Rare examples will exhibit satellitosis, and a distinction from oligodendroglioma can be made by the nuclear pleomorphism of the astrocytic glioma. Neither eosinophilic granular bodies nor Rosenthal fibers are encountered. Furthermore, neither significant mitotic activity nor vascular proliferation is tolerated in the World Health Organization (WHO) grade II designation, their presence relegating the tumor to the higher grades.[1]

The distinction of anaplastic astrocytomas from its lower and higher grade relatives has met with some controversy, as reflected in the variance of cases described in the literature. The anaplastic astrocytoma is known by its frequent mitoses, nuclear pleomorphism, and increased cellular density over those found in the diffuse astrocytoma (see the image below).[1]

Although the World Health Organization does not co Although the World Health Organization does not consider overall cellular density as a useful criterium to grade astrocytic tumors, anaplastic astrocytomas nonetheless frequently demonstrate high cellular density associated with significant nuclear pleomorphism and mitotic activity (hematoxylin & eosin, 40× original magnification).

The Daumas-Duport grading system has organized relatively well-defined features recognizable by most pathologists into a point system that is useful in distinguishing grades II, III, and IV fibrillary astrocytomas. In this system, 1 point (usually nuclear pleomorphism) equals grade II, 2 points (nuclear changes plus mitoses) equals grade III, and 3 or 4 points (plus vascular proliferation and/or necrosis) equals grade 4.[16] Here, the presence of a single mitosis is sufficient to count as 1 point, in contrast to the studies of Giannini and colleagues, who noted that large specimens can have a few mitoses without affecting survival.[17]

In practice, mitotic figures in astrocytomas, even glioblastomas, may be difficult to find. However, the distinction is of significance in that most protocols recommend aggressive chemotherapeutic and radiation therapy to high-grade tumors (grades III and IV), whereas some protocols suggest watchful waiting for low-grade neoplasms (grade II). Here, some authors have recommended that tumors that are excessively cellular with hyperchromatic, elongated nuclei may be designated anaplastic astrocytomas, even in the absence of mitotic figures, if the biopsy is small and the Ki-67 labeling index [LI] is brisk (LI >3-4%). However, these authors also warn about making this evaluation on previously frozen tissue due to the nuclear artifacts induced.[18]

Childhood astrocytomas represent a special subcategory on which many studies are ongoing. To date, infiltrative astrocytomas in children are defined as anaplastic astrocytomas and glioblastomas using similar histologic criteria to those of adult astrocytomas. Great care must be taken in distinguishing among low- and high-grade astrocytomas.[16, 19] Furthermore, the circumscribed gliomas must be distinguished from their more infiltrative relatives; here, radiology is often very helpful.

Gliomatosis cerebri represents a highly invasive aggressive form of glioma defined anatomically as a glioma that infiltrates 2 or more lobes. The majority of these tumors represent grades III and IV astrocytomas. Grade II-appearing lesions may represent sampling errors and those cases exhibiting a relatively low cellular density as may be found in low-grade astrocytomas often but exhibit a disturbingly high mitotic rate or Ki-67 labeling index, which reveals their aggressive biology.[12] For practical purposes, a diagnosis of gliomatosis cerebri implies an aggressive high-grade astrocytoma.

The histologic appearance, both intratumoral and intertumoral, of glioblastomas are highly variable (see the following images). Described histologic variations include fibrillary; gemistocytic; rhabdoid; small, undifferentiated; giant cell; epithelioid; ganglioid; sarcomatoid; oligodendroglial-like; astroblastic; cartilaginous; piloid; schwannian; granular; lipoid; and small stellate, as well as mixtures of these.

Although this degree of endothelial vascular proli Although this degree of endothelial vascular proliferation is not considered sufficient for an unequivocal diagnosis of glioblastoma, its presence should indicate the need for the pathologist to search for necrosis in other fragments of the tumor, a finding that would justify a grade IV designation (hematoxylin & eosin, 40× original magnification).
Some glioblastomas are composed almost entirely of Some glioblastomas are composed almost entirely of large cells, often with prominent nucleoli (hematoxylin and eosin, 40× original magnification).
This glioblastoma is composed of large epithelioid This glioblastoma is composed of large epithelioid cells that are immunoreactive for glial fibrillary acidic protein (GFAP) (hematoxylin and eosin, 40× original magnification).
This high-grade astrocytoma is characterized by sa This high-grade astrocytoma is characterized by sarcomatous metaplasia of astrocytes, resulting in the designation as a gliosarcoma (hematoxylin and eosin, 40× original magnification).

The careful histologic mappings of Burger and colleagues testify to the dramatic cytologic variation manifested by these tumors and their relatively remarkable regional uniformity.[20] However, even in tumors with strong mimicry of other neoplasms, such as metastatic carcinoma, an evaluation of the tumoral margin frequently discloses an infiltrative fibrillary component that identifies the astrocytic nature of the tumor.

In addition to the described cytologic variability of these tumors, there can also be significant histologic variation with occasional presence of metaplastic features, such as smooth muscle, cartilage, liposarcomatous, or primitive neuroectodermal components.[21] Spontaneous intratumoral necrosis was initially established as the diagnostic hallmark of glioblastoma in the 1980s by Nelson et al[22] and Burger et al.[23] Such regions of necrosis were often surrounded by tumor cells in multiple layers, called pseudopalisading necrosis, as seen in the following image.

Pseudopalisading necrosis showing tumor cells orie Pseudopalisading necrosis showing tumor cells oriented in a perpendicular fashion to a region of necrosis in a glioblastoma (hematoxylin and eosin, 40× original magnification).

An interesting corresponding feature of some areas of pseudopalisading necrosis was the presence of surrounding vessels exhibiting profound tortuosities and multiple lumina, which became known as glomeruloid vascular proliferation (see the image below).

This glioblastoma is composed of extensive fibrill This glioblastoma is composed of extensive fibrillary astrocytes and also demonstrates endothelial vascular proliferation (hematoxylin and eosin, 40× original magnification).

The pathogenesis of these vascular deformities are not known but seem to be related to tumoral production of vascular endothelial growth factor (VEGF), and their appearances can be highly variable. Small outcropping tufts of vessels; large, pleomorphic, ballooned channels filled with endothelial tufts and adherent clot; club-shaped enlargements filled with plump endothelial cells; and large glomeruloid masses with flattened endothelial cells can be found in the same tumor. Furthermore the vascular density itself is highly variable and may be an independent prognostic factor.[24]

The most recent WHO catalog designates the vascular change that signifies glioblastoma, even in the absence of necrosis, as "multilayered, mitotically active endothelial cells together with smooth muscle cells/pericytes."[1] However, patients whose glioblastoma diagnosis depended solely on this definition outlive patients whose glioblastomas also exhibit necrosis.[25]

It is also useful to discuss briefly the gliosarcoma, a variant of glioblastoma in which the tumor cells apparently take on the metaplastic appearance of a "fibrosarcoma" or malignant fibrous histiocytoma[26] and exhibit collections of typical malignant astrocytes within pools inside the stromal component. Such tumors may or may not exhibit the typical pseudopalisading necrosis of glioblastomas, but the prognosis is said to be worse than for tumors lacking this sarcomatous, or more accurately, pseudosarcomatous, component.[27]

The cytoplasm of astrocytic neoplasms is probably the most reliable clue in distinguishing these tumors from oligodendroglial tumors, particularly in large specimens. The astrocytic tumor cell cytoplasm is elongated although simplified from that seen in reactive astrocytes with their abundant cytoplasm and complex branching processes. The neoplastic astrocytic cytoplasm is usually located trailing away from the nucleus, resulting in a unipolar appearance. The intercellular spaces exhibit abundant eosinophilic fibrillar cytoplasm that is compact.

An exception to the above rule is found in gemistocytic astrocytomas that reveal a plump cytoplasmic body with an eccentric nucleus. Although anaplastic astrocytomas commonly exhibit some gemistocytic astrocytes, the rare astrocytoma will be composed of a purely gemistocytic tumor cell population.

Whereas historically the gemistocytic astrocytoma has been considered an aggressive astrocytoma with high risk of progression to a grade III tumor, more recent studies indicate that absence of mitotic activity portends a good prognosis and can be justifiably labeled grade II. Even among these cases, however, the clinical history indicates that most grade II gemistocytic astrocytomas progress rapidly to grade III and deserve close clinical follow-up. Also in the consideration of the gemistocytic glioma is the subependymal giant cell astrocytoma of tuberous sclerosis and the hypothalamic hamartoma, both of which exhibit large ganglioid cells reminiscent of gemistocytic gliomas.



All grades of infiltrative astrocytomas exhibit immunoreactivity for glial fibrillary acidic protein, S100, and vimentin. Prognostic significance has been attached to the labeling index by the MIB1 (Ki-67) antibody. Low (< 3%) labeling indices characterize the diffuse astrocytoma. The distinctive feature of anaplastic astrocytomas resides in the high mitotic index and, therefore, brisk Ki-67 labeling index that can range from 3% to 10% (see the following image).[28, 29]

Ki-67 immunohistochemistry reveals cells in any pa Ki-67 immunohistochemistry reveals cells in any part of the cell cycle (including the M phase) except Go. Although this marker gives values higher than the M phase index, the advantage of using the Ki-67 as a proliferation marker is that it correlates with mitotic activity.

However, there are no distinctive differences between the Ki-67 labeling indices of anaplastic astrocytomas and glioblastomas. The recent description of mutations in the isocitrate dehydrogenase gene, IDH1 or IDH2, has led to the identification that the IDH-R132H mutation is found in upwards of 85% of progressive astrocytomas and oligodendrogliomas. This common mutation has been exploited to produce a monoclonal antibody that works in formalin-fixed tissues. The prognostic relevance of this discovery is that R132H-expressing glioblastomas have an apparently better overall survival than IDH wild type anaplastic astrocytomas[30] through a mechanism related to extensive promoter methylation of tumoral DNA.[31, 32]

Another interesting feature of infiltrative astrocytomas is the cross-immunoreactivity of its intermediate filaments with antikeratin antibodies, particularly the AE1/AE3 cocktail, a dilemma that is partially overcome by the use of the CAM 5.2 antibody that recognizes low–molecular-weight keratins.[33]


Molecular Pathology

A high percentage of diffuse astrocytomas and anaplastic astrocytomas exhibit a characteristic mutation in the codon 132 of one copy of the IDH gene, with the most common mutation resulting in the substitution of histidine for arginine,[4] and the acquired ability of the enzyme to catalyze the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG).

The accumulation of 2HG has been demonstrated in individuals with an inherited error in 2HG metabolism, a disease which is also associated with an increase in gliomas.[34] Thus, this new discovery is leading to a better understanding of the early events in gliomagenesis. However, among progressive gliomas, it should come as no surprise that the molecular distinctions among grades II, III, and IV are poorly delineated. It is becoming clear that the progression from grade II to grade IV is accompanied by an increase in the number of cells with polysomy for chromosome 7p and the number of cells with monosomy for chromosomes 10q and 9p.

The oncogenes in these loci are well known and are related to the activation of EGFR-PI3K-PTEN and EGFR/ras/raf signaling pathways and the loss of function of the CDKN2a/b tumor suppressor genes (see the image below).[35]

Fluorescent in situ hybridization (FISH) for epide Fluorescent in situ hybridization (FISH) for epidermal growth factor receptor (EGFR) locus on chromosome 7p demonstrating more than 5 copies per cell in this glioblastoma (EGFR: orange; chromosome 7 centromeric probe: green; 100× original magnification).

While the MET oncogene located on 7q31.2.[36] has been identified as amplified in some studies, recent work suggests amplification does not necessarily result in targetable protein and that demonstration of protein production may be critical to predicting sensitivity to MET inhibitors.[37]

Telomeric-lengthening mechanisms offer intriguing insights into mechanisms driving astrocytoma growth. Alternative lengthening of telomerase under the control of the ATRX and DAXX genes may represent markers of improved survival. This marker is also noted to accompany the IDH1 mutational genotype, another marker of improved survival.[38]

Similarly, more recent studies of over 60 different tumor types throughout the body revealed a high level of mutations in the promoter region of the TERT gene in 83% of primary glioblastomas tested in a pattern that was mutually exclusive of mutations in IDH1 or IDH2 and in ATRX in primary glioblastomas but were concurrent in oligodendrogliomas. The molecular pattern suggests an intriguing mechanism for classification of these tumors with TERT mut/IDH mut found in oligodendrogliomas, TERT wild type/ IDH mut in progressive gliomas, and TERT Mut/ IDH wild type in primary glioblastomas.[8]

The presence of glioblastoma cells with stem cell–like qualities has led to interesting findings. Early experimental studies suggest that the manifestation of radiotherapeutic and chemotherapeutic resistance may be relatable to the percentage of CD133-positive cells in a biopsy sample. These cells appear to be under the control of the HIF-2 alpha gene, a gene that is upstream of the VEGF pathway.[39]

A study concluded that H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, and as a result analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms.[40]



As most diffuse astrocytomas are often treated, the natural history of these lesions is not easily discerned. The available literature does indicate that even the seemingly indolent tumors have a potentially ominous future, with most sources indicating a 6-8 year survival.[1, 11] The location and physical association of these tumors clearly alters the therapeutic options and ultimate prognosis.

The treatment of choice is surgical debulking; however, involvement of deep gray nuclear structures, brainstem, etc, is associated with such a significant morbidity that it prevents such palliative therapy.[14] In general, the survival of patients with anaplastic astrocytoma is 2.5 years, again intermediate between diffuse astrocytoma and glioblastoma, with glioblastoma patients surviving for about 1 year.[2, 3]

Inadequate tumoral sampling with undergrading of some glioblastomas as anaplastic astrocytoma may occur, especially when diagnoses are based on tissues obtained from stereotactic biopsies. In view of the heterogeneous nature of these tumors, tissue diagnoses based on specimens from radical resections are more likely to yield accurate diagnoses.[41] Incompletely resected tumors are associated with poorer outcome in spite of aggressive chemotherapy and radiation therapy.[42]

Age younger than 50 years, good Karnofsky score, presence of an oligodendroglioma component, and absence of ring enhancement are favorable prognostic features.[43, 44, 45] Anaplastic astrocytomas are more responsive to chemotherapy than glioblastomas,[12, 46] a finding that seems to correlate with the absence of the methylguanine methyltransferase DNA repair enzyme that is responsible for demethylating methylguanine adducts induced by alkylating chemotherapeutic agents.[46, 47] Also, as mentioned above, the presence of IDH1/2 mutations also confers a better-than-average prognosis on patients whose tumors bear the change. While it is found in upwards of 85% of lower-grade gliomas, it is only found in 5% of glioblastomas.[30]


Differential Diagnosis

The following conditions are considered in the differential diagnosis:

  • Anaplastic meningiomas

  • Ganglioglioma/glioneuronal tumors

  • Hypothalamic hamartoma

  • Macrophage-rich lesions, including stroke and multiple sclerosis

  • Metastatic malignancies

  • Oligodendroglioma

  • Pleomorphic xanthoastrocytoma

  • Primary cerebral and skull-based sarcomas

  • Progressive multifocal leukoencephalopathy (PML)

  • Radiation necrosis