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 [1] ).
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 earliest version of the 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.
In 2016, the WHO introduced molecular features into the classification of gliomas (IDH mutation and the deletion of 1p/19q) and paved the way to a growing amount of research lines. In the last few years, a great shift in our understanding of these tumors has taken place, and the standard diagnostic evaluation of gliomas must now include a molecular assessment. In fact, today we know that these molecular diagnostic markers are crucial for primary classification, which should be based primarily on mutational status rather than solely on histological grade. [1]
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. [2] These new molecular and genetic parameters are now integrated in our decision-making paradigm regarding diagnosis, prognosis, and treatment. The grading system in the 2021 WHO classification of CNS tumors was adapted to these conditions, as previous grading systems would equally standardize prognostic and clinico-biological behavior of the tumors based on grading (I–IV). Today, prognosis is more closely associated to molecular fingerprinting than to morphology and histology; however, grading within subtypes takes place within the whole spectrum of characteristics in the tumor. Immunohistochemistry and cytogenetics provide an accurate diagnosis for most patients, whereas chromosomal and gene arrays provide more complete diagnostic information for some tumors. [3]
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.
Low-grade astrocytomas generally cause symptoms by perturbing cerebral function (ie, seizures), elevating intracranial pressure (ICP) by either mass effect or obstruction of cerebrospinal fluid (CSF) pathways (ie, hydrocephalus), causing neurologic deficits (ie, paralysis, sensory deficits, aberrant behavior), headaches, and endocrine abnormalities. The location of the tumor may have a direct relationship with the signs and symptoms present in each patient. Some tumors are described according to the specific locations of the brain in which they arise.
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. However, there is not a precise elucidation of these mechanisms prompting the development of these tumors in specific areas of the brain, and thus, they should be considered as examples only.
The most recent classification of tumors for low-grade astrocytomas is elaborated in the sections that follow.
Adult-type diffuse gliomas
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.
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Adult diffuse astrocytoma IDH-mutant (WHO grade 2): Lesion with diffuse infiltration, IDH-1 or IDH-2 mutant, and absence of 1p/19q deletion. ATRX and/or TP53 mutation is frequent. Can be observed in Li-Fraumeni syndrome with TP53 mutation. Well differentiated and no anaplastic features. Absence of necrosis, microvascular proliferation, nuclear atypia, and negative deletions of CDKN2A and/or CDKN2B.
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Gemistocytic astrocytoma: see Histology
Pediatric-type diffuse gliomas
Pediatric-type diffuse gliomas are classified into pediatric-type diffuse low-grade glioma and pediatric-type diffuse high-grade glioma. In this section we discuss the low-grade subtypes of these tumors.
Pediatric diffuse low-grade gliomas
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Pediatric diffuse astrocytoma, MYB or MYBL1 altered (WHO grade 1): Cortical and subcortical components. There are no features of anaplasia. No mutations in IDH genes are observed with structural alterations of MYB or MYBL1.
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Angiocentric glioma (WHO grade 1): Composed of thin bipolar cells in perivascular areas. The majority present with MYB:QKI gene fusion or at least an MYB alteration.
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Polymorphous low-grade neuroepithelial tumor of the young (WHO grade 1): Lesion with diffuse growth behavior with oligodendroglioma-like cells and calcifications. MAPK pathway-activating abnormalities.
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Diffuse low-grade glioma, MAPK pathway altered: Diffuse growth pattern with astrocytic and oligodendroglioma components. Alterations in MAPK pathway. H3 and IDH wildtype. Characterized by the presence of an internal tandem duplication or mutations in tyrosine kinase domains (FGFR1 of BRAF V600E).
Pediatric diffuse high-grade gliomas
These include diffuse midline glioma (H3 K27-altered), diffuse hemispheric glioma (H3 G34-mutant), diffuse pediatric-type high-grade glioma (IDH-wildtype and IDH-mutant), and infant-type hemispheric glioma.
Circumscribed astrocytic gliomas
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).
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Pilocytic astrocytoma (WHO grade 1): Associated with MAPK alterations, most often KIAA1549/BRAF fusions. However, other BRAF alterations can be observed. Typically, combined cystic and nodular lesions are observed.
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Pilomyxoid astrocytoma (WHO grade 1):This tumor is a pilocytic astrocytoma with anaplastic features in histologic analysis.
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Pleomorphic xanthoastrocytomas (WHO grade 2): BRAF V600E mutation is characteristic combined with CDKN2A or CDKN2B deletion.
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Subependymal giant cell astrocytoma (SEGA) (WHO grade 1): Multinodular, solid periventricular tumors made of ganglion-like astrocytes. A strong association is observed with Tuberous sclerosis.
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Astroblastoma MN1 altered (grade not established): Tumors with solid and/or cystic components. Perivascular pseudorosettes and MN1 alteration are essential for diagnosis.
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Chordoid glioma (WHO grade 2): Well-circumscribed lesion arising in the anterior portion of the third ventricle. Mutations in the PRKCA gene.
Epidemiology
Frequency
United States
The overall incidence of all primary malignant and non-malignant brain and other CNS tumors is 24.83 cases per 100,000 people (6.94 per 100,000 for malignant tumors and 17.88 per 100,000 for non-malignant tumors). [4] In children and adolescents, the rate of primary malignant and non-malignant tumors is 6.13 per 100,000. [4] Of all glioma subtypes, diffuse astrocytomas represent 9.1% and pilocytic astrocytomas 5.1%. [5]
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 includes tumors derived from oligodendrocytes as well as mixed glial-neuronal tumors.
Gliomas can be found more frequently in patients 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, 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. [6]
Mortality/morbidity
Five-year survival after diagnosis of a non-malignant CNS tumor is 91.9%. Survival is higher in younger age groups compared to in patients older than 40 years (97%–98% versus 90.4%, respectively). [4] However, 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. [7] 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%. [8] 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 rather as a chronic disease state that continually invades and compromises the brain until a potential malignant transformation occurs. [9]
Race
For primary tumors in the CNS, there is a slight increase in incidence in non-Hispanic patients (25.24 per 100,000 patients) compared to Hispanic patients (22.61 per 100,000 patients). In children and adolescents, a greater incidence is reported in White patients (6.36 per 100,000 patients) compared to Black patients (4.79 per 100,000 patients). Similarly, non-Hispanic patients (6.38 per 100,000 patients) showed more incidence than Hispanic patients (5.33 per 100,000 patients). [4]
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 (27.85 per 100,000 tumors) than in males (21.62 per 100,000 tumors). [4]
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. [10] 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.
Prognosis
Prognosis greatly depends on the pathology of the tumor. Taking many published series together, median survival duration is approximately 7.5 years. However, patients with pilocytic astrocytomas who undergo gross total resection can expect a cure. For low-grade astrocytomas that continue their relentless slow growth, progressive neurologic deficit may occur over a period of years.
In a large, multi-institutional study of patients with low-grade gliomas, Chang et al found that the University of California, San Francisco (UCSF) preoperative scoring system accurately predicted overall survival (OS) and progression-free survival (PFS). The 537 patients in the study were assigned a prognostic score based upon the sum of points assigned to the presence of each of the 4 following factors: (1) location of tumor in presumed eloquent cortex, (2) Karnofsky Performance Scale (KPS) Score ≤ 80, (3) age > 50 years, and (4) maximum diameter > 4 cm. Stratification of patients based on scores generated groups (0–4) with statistically different OS and PFS estimates (p < 0.0001). The 5-year cumulative OS probabilities stratified by score group were as follows: score of 0, 0.98; score of 1, 0.90; score of 2, 0.81; score of 3, 0.53; and score of 4, 0.46. [11]
The molecular classification of low-grade diffuse gliomas [12] has shown that some mutations correlate with survival. The median survival of patients with TP53 mutation with or without IDH1/2 mutation was significantly shorter than that for patients with 1p/19q loss with or without IDH1/2 mutation. Multivariate analysis with adjustment for age and treatment confirmed these results and revealed that TP53 mutation is a significant prognostic marker for shorter survival and 1p/19q loss for longer survival, while IDH1/2 mutations are not prognostic.
For the pediatric population the prognosis is different. In cases of complete resection, prognosis tends to be very good and close to complete cure with need for strict followup only. In cases of tumor remnant or inability to perform surgical resection (ie, deep-seated lesions), mortality tends to occur either from tumor-related factors or treatment morbidity. In one summary, [13] researchers found that during a 30-year period the mortality rate was 12%, with a median time to death from diagnosis of 4.02 years (range, 0.21–24 years). Yet, their study mixed different kinds of tumors. In the case of tumor harbor BRAF mutation, we have an efficient tool that can either treat the lesion for complete resolution or reduce its size making it amenable to safer resection. Study is still ongoing in this regard.
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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.
