Background
Low-grade astrocytomas are a heterogeneous group of intrinsic central nervous system (CNS) neoplasms that share certain similarities in their clinical presentation, radiologic appearance, prognosis, and treatment. The most common intrinsic brain tumor, glioblastoma multiforme, is high grade and malignant. This contrasts with low-grade astrocytomas, which are less common and therefore less familiar to practitioners.
Improvements in neuroimaging permit the diagnosis of many low-grade astrocytomas that would not have been recognized previously. Low-grade astrocytomas are, by definition, slow growing, and patients survive much longer than those with high-grade gliomas. Proper management involves recognition, treatment of symptoms (eg, seizures), and surgery, with or without adjunctive therapy. Low-grade astrocytomas are found along the central nervous system (brain and spinal cord). In the past few years, new observations concerning molecular precursors and molecular diagnostics in adult and pediatric populations with low-grade gliomas have yielded a change in the pathological classification of all gliomas including astrocytomas (eg, World Health Organization [WHO] classification [35] ).
Pathophysiology
Low-grade astrocytomas are primary tumors (rather than extraaxial or metastatic tumors) of the brain. Astrocytomas are one type of glioma, a tumor that forms from neoplastic transformation of the so-called supporting cells of the brain, the glia or neuroglia. Gliomas arise from the glial cell lineage from which astrocytes, oligodendrocytes, and ependymal cells originate. The corresponding tumors are astrocytomas, oligodendrogliomas, and ependymomas. Grading of a glioma is based on the histopathologic evaluation of surgical specimens. The old World Health Organization (WHO) scheme was based on the appearance of certain characteristics only: atypia, mitoses, endothelial proliferation, and necrosis. These features reflect the malignant potential of the tumor in terms of invasion and growth rate. Tumors without any of these features were classified as grade I. Tumors with cytological atypia alone were considered grade II (diffuse astrocytoma). Those that show anaplasia and mitotic activity in addition to cytological atypia were considered grade III (anaplastic astrocytoma) and those exhibiting all of the previous features as well as microvascular proliferation and/or necrosis were considered grade IV. [1]
In the last few years, as mentioned, a great shift in our understanding of these tumors occurred and the standard diagnostic evaluation of gliomas must now include a molecular assessment of isocitrate dehydrogenase (IDH) mutations and codeletion of chromosome arms 1p and 19q to be considered complete. [38, 39, 40, 41, 42] In fact, today we know that these molecular diagnostic markers are crucial for our primary classification, which should be based primarily on mutational status, rather than solely on histological grade. [35] Two phase III trials have indicated that although initial treatment with either chemotherapy or radiation therapy might produce similar results overall, outcomes vary by molecular diagnosis. [69] These new molecular and genetic parameters are now integrated in our decision-making paradigm regarding diagnosis, prognosis, and treatment. Prognosis is more closely associated to the molecular fingerprinting than to morphology and histology, however, the previous grade classification remains relevant as well. Immunohistochemistry and cytogenetics provide an accurate diagnosis for most patients, whereas chromosomal and gene arrays provide more complete diagnostic information for some tumors. [38]
Another important distinction is between pediatric and adult low-grade astrocytomas. Pediatric low-grade astrocytomas exhibit markedly different molecular alterations, clinical course, and treatment than their adult counterpart.
Grades I and II astrocytomas comprise the low-grade group of astrocytomas.
A subset of low-grade astrocytomas may have features of high-grade lesions including endothelial proliferation and necrosis, although they remain slow growing and well circumscribed. This subset comprises juvenile pilocytic astrocytoma (JPA), pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma (PXA), and subependymal giant-cell astrocytoma (SEGA).
Low-grade astrocytomas generally cause symptoms by perturbing cerebral function (i.e. seizures), elevating intracranial pressure (ICP) by either mass effect or obstruction of cerebrospinal fluid (CSF) pathways (i.e. hydrocephalus), causing neurologic deficits (i.e. paralysis, sensory deficits, aberrant behavior), headaches and endocrine abnormalities.
Most low-grade astrocytomas tend to occur in the lobes of the cerebral hemispheres. Although pilocytic astrocytomas can occur supratentorially, the cerebellum is their most common location especially in children. Pleomorphic xanthoastrocytomas (PXA) are more common in the supratentorial space in a characteristic superficial location, which involves both the cerebrum as well as the overlying meninges. Subependymal giant-cell astrocytomas (SEGA) are found most commonly in the wall of the lateral ventricles and are associated with tuberous sclerosis, an autosomal dominant disease that causes growth of benign tumors in different organ systems.
The main group of low-grade astrocytomas are diffuse astrocytomas. One of the important features to differentiate diffuse astrocytomas from oligodendrogliomas is the lack of 1p/19q co-deletion. The latest 2016 WHO classification is based on molecular subtyping:
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Diffuse astrocytoma, IDH-mutant (WHO grade II) is described as a diffusely infiltrating astrocytoma with a mutation in either the IDH1 or IDH2 gene. The histology of this type of tumor is typically composed of cells with moderate pleomorphism, and shows advanced astrocytic differentiation. It has a relatively slow growth pattern. Other important stains that support the diagnosis are the presence of TP53 and ATRX mutations.
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Gemistocytic astrocytoma, IDH-mutant (WHO grade II) remains the only histopathologically defined subtype of astrocytoma, and accounts for ~10% of WHO grade II diffuse astrocytomas. This histological subtype is known for being described as having a higher tendency for malignant transformation, however, it is not yet known what the risk in correlation to IDH mutation is.
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Diffuse astrocytoma, IDH-wild-type is a diffusely infiltrating astrocytoma without mutations in the IDH genes. This diagnosis is rare and likely to change in the next release of the WHO classification. This specific subtype harbors a variety of tumors that can be again reclassified by future genetic and molecular studies. [39, 40]
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Diffuse astrocytoma, NOS is a tumor with histopathological features of a diffuse astrocytoma in which IDH mutation status has not been fully assessed (ie, not tested, lost, not known, etc.). The WHO states the use of this subgroup should be minimal and promotes its disuse.
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Midline diffuse low-grade gliomas should be distinguished from regular diffuse astrocytomas by mutation in histone H3 (Lys27Met mutation). Histological grade does not predict the outcome of the highly aggressive tumors with this mutation.
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Others is a group that includes pilocytic astrocytoma, pleomorphic xanthastrocytoma, and subependymal giant cell astrocytoma. In the latest classification, some tumors that were once known as different sub-groups, for example, diffuse astrocytomas and oligodendrogliomas, were reorganized under the same subtype (diffuse astrocytoma depends on the IDH mutation status). On the other hand, a more obvious differentiation has been established between some tumors that were once thought to be of similar subtypes like diffuse astrocytomas and pilocytic astrocytomas. This classification leaves those astrocytomas that have a more circumscribed appearance, lack IDH gene family mutations, and frequently have BRAF mutations (pilocytic astrocytoma, pleomorphic xanthastrocytoma) or TSC1/TSC2 mutations (subependymal giant cell astrocytoma) distinct from the diffuse gliomas. [35]
Epidemiology
Frequency
United States
The overall incidence of all primary malignant and non-malignant brain and other CNS tumors is 22.36 cases per 100,000 people (7.18 per 100,000 for malignant tumors and 15.18 per 100,000 for non-malignant tumors for a total count of 250,211 incident). [37] In children, the rate of primary malignant and non-malignant tumors is 5.67 per 100,000. Of all glioma subtypes, diffuse astrocytomas represent 9.1% and pilocytic astrocytomas 5.1%. [2] These numbers are derived from the prior classification system and do not reflect the latest changes in the system. Although these numbers represent an approximate estimation of the epidemiology of low-grade astrocytomas, it is important to note that there are no studies that have addressed this group in an isolated fashion. This is in part due to the fact that low-grade astrocytomas are generally categorized as part of a broader group collectively known as low-grade gliomas which include tumors derived from oligodendrocytes as well as mixed glial-neuronal tumors.
Gliomas are associated with certain phakomatoses, especially neurofibromatosis type 1 (NF-1). Low-grade astrocytomas occur more commonly in these patients, particularly in the optic nerves and optic chiasm. As mentioned before, subependymal giant-cell astrocytomas are found almost exclusively in patients with tuberous sclerosis.
International
The incidence of low-grade astrocytomas has not been shown to vary significantly by nationality. However, studies examining the incidence of malignant CNS tumors have shown some differences based on nationality. Since some high-grade lesions arise from low-grade tumors, these trends are worth mentioning. Specifically, the incidence of CNS tumors in the United States, Israel, and the Nordic countries is relatively high, while Japan and other Asian countries have a lower incidence. These differences probably reflect some biological disparities, as well as discrepancies in pathologic diagnosis and reporting.
A study of the incidence of brain tumors in Europe concluded that of all glial tumors, the astrocytic subtype is the most common with a reported incidence of 4.8 cases per 100,000 people per year. This number represents all astrocytic tumors without a specific mention of low-grade cases. [3]
Mortality/Morbidity
Due to the inherent differences in biology and natural history of this heterogeneous patient population, it is difficult to determine an exact mortality rate for low-grade astrocytomas. The update in classification and the new molecular subtyping (ie, change of the once called diffuse pontine glioma with midline glioma) stress the need for new studies and statistics focusing on the different subtypes.
Pilocytic tumors can potentially be cured with surgical resection, and in specific cases where resection is not amenable, these can be treated with BRAF inhibitors. [43] Pilocytic astrocytomas have a 25-year survival rate of 95% when they are cystic and well circumscribed. For cerebellar tumors that are completely resected, the 10-year survival rate is almost 100%. [4] Although survival is affected by some prognostic factors, average overall survival from diagnosis is about 5–6 years, ranging from 3 to 10 years. Based on these numbers, these tumors should not be considered benign tumors, but a chronic disease state that continually invades and compromises the brain until a potential malignant transformation occurs. [44]
Race
No clear evidence has been published that low-grade astrocytomas are more common in any racial or ethnic group. In the United States, malignant CNS tumors are slightly more common in whites than in blacks. Whether this applies to low-grade tumors remains to be studied.
Sex
There is a slight female predominance in the incidence of primary brain and CNS tumors according to the latest report of the Central Brain Tumor Registry of the United States (CBTRUS). The rate is higher in females (24.46 per 100,000 tumors) than in males (20.10 per 100,000 tumors). [37, 2]
Age
The median age of patients diagnosed with a low-grade astrocytoma is approximately 35 years old, which is a younger age than that of patients with malignant gliomas. Juvenile pilocytic astrocytomas have a median age at diagnosis that is about a decade younger than other low-grade astrocytomas. The incidence of primary brain tumors, malignant astrocytomas in particular, is increasing in elderly patients. [5] Whether this is a true increase in incidence or simply the result of higher rates of detection due to increased imaging or reporting is unknown.
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A 28-year-old male taxi driver presented to the emergency department after having a seizure. Noncontrast head CT scan was obtained showing the typical appearance of a low-grade astrocytoma. The lesion in the mesial left frontal lobe was hypodense on CT scan.
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Preoperative MRI of the brain of a 28-year-old male taxi driver who presented to the emergency department after having a seizure. On T1-weighted sequences, the tumor does not enhance and shows decreased signal intensity compared to normal brain. These findings are consistent with low-grade astrocytoma.
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For tumors, MRI has the advantage of showing the lesion in multiple planes. This image, a T1-weighted sagittal image of the brain of a 28-year-old male taxi driver who presented to the emergency department after having a seizure, shows the tumor along the mesial aspect of the frontal lobe. Note that mass effect is minimal, typical of a low-grade lesion.
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T2-weighted sequences of an MRI of the brain of a 28-year-old male taxi driver who presented to the emergency department after having a seizure show increased signal intensity compared with normal brain. The radiologic appearance is typical of low-grade astrocytoma.
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A 9-year-old boy presented with headaches and gradual onset of right hemiparesis. MRI of the brain was obtained. The T2-weighted sequence in this MRI shows a tumor in the left thalamus, which is a typical location for a juvenile pilocytic astrocytoma. Note the relatively well-circumscribed nature of the lesion.
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Coronal T1-weighted gadolinium-enhanced MRI of the brain shows the tumor of a 9-year-old boy who presented with headaches and gradual onset of a right hemiparesis. Note the heterogeneous enhancement of the tumor.
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Sagittal T1-weighted MRI of the brain shows juvenile pilocytic astrocytoma of a 9-year-old boy who presented with headaches and gradual onset of right hemiparesis. Stereotactic surgery has made resection of these low-grade tumors in this deep location feasible.
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A 3-year-old boy presented with speech regression. MRI of the brain revealed a tumor in the left mesial temporal lobe. This T1-weighted gadolinium-enhanced image shows an enhancing tumor involving the hippocampus, uncus, and amygdala. The surgical pathologic studies revealed a low-grade mixed tumor of astrocytes and atypical neurons, a ganglioglioma.
