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),
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).
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.
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.
These findings were also reported in a 2013 study.
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.
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.
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.
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.
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
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.
Glioblastomas can be found in association with Li-Fraumeni syndrome and Lynch syndrome.
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.
Among all diffuse astrocytomas, there is a two-fold higher predominance in white individuals (0.45) compared with black individuals (0.20).
Among anaplastic astrocytomas and glioblastomas, there is a moderate male-to-female predominance of approximately 1.6:1.
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.
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.