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] ).
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.
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.
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
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.
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.
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.
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).
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.
Pilomyxoid astrocytoma (WHO grade 1):This tumor is a pilocytic astrocytoma with anaplastic features in histologic analysis.
Pleomorphic xanthoastrocytomas (WHO grade 2): BRAF V600E mutation is characteristic combined with CDKN2A or CDKN2B deletion.
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.
Astroblastoma MN1 altered (grade not established):Tumors with solid and/or cystic components. Perivascular pseudorosettes and MN1 alteration are essential for diagnosis.
Chordoid glioma (WHO grade 2): Well-circumscribed lesion arising in the anterior portion of the third ventricle. Mutations in the PRKCA gene.
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 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.
There are no specifics factors in the patient’s history that are pathognomonic for low-grade glioma. The history, however, should alert the clinician to the presence of a neurologic disorder and the need for an imaging study. Characteristically, low-grade gliomas present with headache, focal deficit, and/or most notably seizures. The latter can be present in up to 80% of patients.[14] Other common symptoms are secondary to mass effect of the lesion on the surrounding brain parenchyma (ie, hemiparesis, sensory deficits, alterations in speech, or visual field defects).
A small percentage of low-grade astrocytomas present in the spinal cord of both children and adults. The history of these tumors is characterized by a slow onset of back pain and neurologic deficits. The pain is usually localized over the region of the tumor, which is most common in the cervicothoracic area. Neurologic symptoms include paresthesias in the arms or legs; weakness, objective numbness, and bowel or bladder symptoms may also be seen.
Patients suffering from low-grade gliomas typically exhibit three clinical stages.[15, 9, 16] The first is a pre-symptomatic stage in which the tumor slowly infiltrates the brain, yet the patient remains largely asymptomatic. This period is usually long, but exceptions do exist. The second is a symptomatic stage that classically starts with a first-time seizure or subtle story of recurrent episodes suggestive of mild evolving epileptic activity secondary to the tumor. Subtle changes in cognitive ability and personality also emerge. The time period for this symptomatic stage is usually between 5 and 10 years. The third state is malignant transformation. Patients deteriorate in their neurological functions in a gradual but progressive fashion, eventually leading to death. This transformation tends to occur as a result of a multifactorial process, including tumor-specific molecular biology and genetics, as well as tumor burden.
This understanding has led to a treatment paradigm that advocates aggressive early treatment and moves away from the watchful waiting approach that was common in the past.
A comprehensive neurological exam must be performed on any patient who is suspected of harboring an intracranial lesion. In most centers specialized in neuro-oncology, it is common to use the Karnofsky Performance Score (KPS) to assess the functional status of the patient before, during, and after treatment. Cranial nerve deficits are not pathognomonic of low-grade gliomas, but the presence of multiple cranial neuropathies is common with brainstem lesions. The motor and sensory exam may disclose hemiparesis, as well as hemisensory deficits, increased deep tendon reflexes, and signs of corticospinal tract involvement (ie, Babinski reflex). In patients with posterior fossa lesions (which are more common in children), signs of cerebellar involvement like ataxia, intention tremor, and dysdiadochokinesia are common.
Preoperative neuropsychological assessment may be indicated in patients with a lesion close to or in an eloquent region. Eloquent regions are areas of the brain that control speech, motor and sensory functions, visual perception, and higher cortical functions. Lesions involving these regions are more prone to undergo awake craniotomy and transoperative cortical mapping.
The etiology of low-grade gliomas is poorly understood. There are numerous studies published throughout the literature that have attempted to link specific environmental factors with the subsequent development of brain tumors. Although many potential associations have derived from these studies, the only clear predisposing factor is prior exposure to ionizing radiation. Other factors like socioeconomic status, occupational exposure, and the ingestion of certain types of food (those containing a high concentration of N- nitroso compounds) have not shown conclusively that they could be linked to an increase in the development of gliomas.[17]
Definitive genetic associations have been made between conditions like neurofibromatosis (NF-1 and NF-2), tuberous sclerosis, Li-Fraumeni syndrome, and Turcot syndrome with the development of gliomas.
No specific laboratory test is available for the diagnosis or followup of low-grade gliomas. There are promising studies that aim to detect circulating tumor DNA in human malignancies. Although this technology has not yet been applied to low-grade gliomas, it could potentially be implemented in the future as a screening, diagnostic, and/or followup tool.[18]
Both CT scan and MRI can aid in the diagnosis of low-grade gliomas. Generally, MRI with and without contrast is considered the study of choice. However, in an emergency setting a noncontrast CT scan may be ordered first.
Computed tomography
Patients with new-onset headache, seizure, weakness, or numbness frequently undergo a noncontrast CT scan first. A typical CT finding of a low-grade glioma is a region of lower attenuation than the surrounding brain (see image below). A mild mass effect may be noted. Secondary hydrocephalus can be confirmed in some cases. Low-grade astrocytomas usually will not harbor calcifications like other members of the low-grade glioma family, like oligodendrogliomas. Low-grade astrocytomas are usually non-enhancing lesions, although the presence of contrast enhancement doesn’t preclude their diagnosis (especially in pediatric patients).
PET and SPECT
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging sometimes are used to try to differentiate low-grade gliomas from either high-grade tumors or other types of pathology. Typically, low-grade gliomas show hypometabolism via PET or SPECT while high-grade gliomas are hypermetabolic. This information may be useful in guiding further therapy.
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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....
Magnetic resonance imaging
On MRI, low-grade astrocytomas show decreased signal relative to surrounding brain on T1 sequences (see following images).
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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 seque....
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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 mal....
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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....
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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....
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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-enh....
On T2 sequences, higher signal reflects both the tumor and surrounding edema (see following images). Pilocytic astrocytomas often are associated with a cyst, which may be particularly prominent on T2-weighted sequences.
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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 i....
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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 ....
One of the important sequences is T2 FLAIR (fluid-attenuated inversion recovery) because it has been shown to be a good tool for diagnosis as well as for followup of low-grade gliomas with high sensitivity for tumor recurrence.[19]
Functional magnetic resonance imaging (fMRI) can provide information about the localization and relationship of a low-grade glioma and eloquent structures such as speech centers and motor pathways. fMRI has been shown to be a valuable tool especially when the tumor is on the language-dominant hemisphere. This may help in surgical planning. The use of digital tractography (DTI, diffuse tensor imaging) has also become a popular tool in recent years and can give good preoperative assessment regarding the location of important tracts, like motor or optic pathway.
A spine MRI is also the study of choice if an intramedullary low-grade astrocytoma is suspected. On MRI, widening of the spinal cord and frequently an associated cyst are noted. The tumor may show variable degree of enhancement. T2 changes as well as FLAIR changes are important for diagnosis and follow-up.
Imaging studies are routinely used to assess tumors in the central nervous system. As with molecular characterization with genomics or proteomics, imaging studies can aid in the typification of the lesions, providing information through a qualitative description to unveil the biology of the tumors. This discipline is known as radiomics. As previously mentioned, radiomics takes qualitative findings to make a suggestive diagnosis. This is supported by mathematical formulas and computer algorithms encasing a quantitative analysis of images correlated with their outcomes.[20]
Studies have pointed out the efficient use of radiomic features in assessing intracranial masses, being able to distinguish between different entities, such as metastases from high-grade gliomas.[21] Specific radiomic features may allow the clinician to proceed with tailored therapy for the patient, making it a highly valued tool in the treatment of CNS tumors.[22, 23]
Radiomics in low-grade astrocytoma
Evidence has pointed out possible radiomic features found in low-grade astrocytoma. Comparisons of these features can be made with different entities such as anaplastic astrocytoma or high-grade astrocytoma. Low-grade astrocytoma can be misdiagnosed as anaplastic astrocytoma and vice versa due to similarities often seen in MRI imaging.[24] The use of specific radiomic features might help to mitigate these issues; compared to conventional radiologic analysis, radiomics eliminate intra and interobserver variability in the analysis of different features in brain tumors such as shape, size, enhancement, borders, heterogeneity, etc.[25]
Radiomics have been demonstrated to be useful in discriminating between IDH-mutant non-codeleted 1p/9q tumors or astrocytomas and IDH-mutant codeleted 1p/9q tumors or oligodendrogliomas. Similarly, authors have developed models to distinguish O6-methylguanine-DNA methyltransferase (MGMT) status using a T2-weighted flair and apparent diffusion coefficient (ADC) to describe a determined radiomics signature to the MGMT promoter.[26, 27] Models have been successfully developed to predict overall survival in low-grade gliomas.[28]
Electroencephalography (EEG) may be performed on a patient with new-onset seizures. However, no EEG findings are specific to low-grade gliomas. Nonetheless, generalized, diffuse slowing, and/or epileptogenic spikes can be seen over the area of the tumor.
Neuropsychological evaluation is important and can help to evaluate pre and postoperative function. Subtle changes in repeated neuropsychological testing have been shown to correlate with tumor progression.
Lumbar puncture is generally contraindicated in patients with elevated intracranial pressure, which may occur in the setting of a brain tumor. Cerebrospinal fluid (CSF) studies do not aid in the diagnosis of low-grade astrocytomas.
The histologic findings in low-grade astrocytomas vary according to the specific tumor type. As previously reviewed, these lack high-grade features like necrosis, microvascular proliferation, and high mitotic indices.
Adult diffuse astrocytoma IDH-mutant (WHO grade 2):Well-differentiated glial cells with diffuse infiltration in the parenchyma. Typically, cohesion between cells is absent, forming a loose structure. Mildly to moderately increased cellularity compared to normal brain. Neoplastic astrocytes differ mainly on nuclear characteristics with enlarged nuclei and irregular contours, hyperchromasia, and an uneven chromatin pattern. Nucleoli display no difference and are not visible at most times. Mitotic activity is absent. Microcystic change in the tumor stroma is a frequent feature.
Gemistocytic astrocytoma: IDH-mutant astrocytoma with > 20% of gemistocytic astrocytes. Gemistocytes are characterized by abundant and glassy cytoplasm displacing the nucleus to the periphery.
Pediatric diffuse astrocytoma, MYB or MYBL1 altered (WHO grade 1): There is a proliferation of monomorphic glial cells in a diffuse fibrillar matrix. Numerous entrapped neurons are observed with neurofilament immunostaining.
Pilocytic astrocytoma (WHO grade 1): Low to moderate cellularity with the presence of bipolar piloid cells with long hair-like processes and Rosenthal fibers. A myxoid background can be observed with microcystic changes. Degenerative changes such as calcifications, hyalinized vessels, and hemorrhages are common. Nuclei are round to elongated. Large cells with lobulated or horseshoe nuclei can be normally displayed (referred to as pennies-on-a-plate pattern).
Pilomyxoid astrocytoma (WHO grade 1): These tumors share many of the features of pilocytic astrocytomas. They are dominated by the presence of a mucoid matrix, monomorphous bipolar cells, and an angiocentric cell arrangement. These tumors lack Rosenthal fibers.
Pleomorphic xanthoastrocytomas:These tumors have a variable histological appearance. The term xanthoastrocytoma is derived from the presence of xanthomatous cells, which show intracellular accumulation of lipids.
Subependymal giant cell astrocytoma (SEGA) (WHO grade 1): Circumscribed tumors with a wide spectrum of glial cells. Cells might appear wide with abundant cytoplasm to spindle-shaped cells and gemistocyte-like cells. Clusters and perivascular rosette-like patterns can be seen (similar to ependymoma). S100 and synaptophysin stains positive.
Astroblastoma MN1 altered (grade not established):Composed of round, cuboid, or columnar cells. Histologic hallmark is an astroblastic pseudorosette.
Chordoid glioma (WHO grade 2): Solid lesion with a mucinous stroma and clusters of epithelioid cells. Russell bodies are common.
Angiocentric glioma (WHO grade 1):Thin bipolar cells in perivascular spaces and entrapped neurons.
Polymorphous low-grade neuroepithelial tumor of the young (WHO grade 1): Predominantly with oligondendroglioma-like components. Calcifications often are confluent.
Diffuse low-grade glioma, MAPK pathway altered:Cells with a bland appearance, mildly atypical glial cells, and entrapped parenchyma.
Molecular and genetic landscape
The majority of pediatric low-grade gliomas share alterations in MAPK/ERK (MEK) alterations, which affect cell division, differentiation, and transcription, among other molecular processes. Many of the genes or molecular changes seen in low-grade gliomas ultimately converge in the MAPK pathway.[29]
The BRAF proto-oncogene is part of the MEK signaling pathway. The first description of the mutant form of this gene known as BRAF V600E was made in 2013, corresponding to a three-amino-acid insertion increasing ERK activation. BRAF V600E and BRAF fusion with KIAA1549 are the most frequent BRAF disarrays in low-grade gliomas, both genetic hallmarks in tumors such as pilocytic astrocytoma. BRAF V600EE mutations are frequently paired with further alterations such as CDKN2A, FGFR1, KRAS, and H3F3A. Patients with BRAF-KIAA1549 fusion tend to have a better outcome than patients with BRAF V600E mutations. However, tumors with mutations involving BRAV V600E alterations coupled with disarrays in CDKN2A can undergo malignant progression and worse outcomes in terms of survival and progression of the disease.
Similarly, the NF1 gene carries downregulation of RAS in the MEK pathway; thus, mutations in this gene, in neurofibromatosis type 1, allow an increased activation of the MEK signaling pathway as RAS is constantly activated. Tumors in NF-1 mutations are most commonly observed in the hypothalamus and optic pathways. Targeted therapy with pharmacological agents for NF-1 patients are already available and FDA-approved for specific treatment of patients with these mutations (eg, selumetinib).
FGFR signaling can trigger activation of MAPK and PI3K pathways. FGFR can be involved in alterations, typically involving fusions, duplications, and hotspot mutations with other genes. These dysregulations prompt the occurrence of cellular events that favor tumorigenesis through activation of MAPK/PI3K target of rapamycin (mTOR). Patients with FGFR mutations can face further progression; however, these mutations are not commonly involved in increased mortality. Alterations in FGFR can be seen in diffuse midline gliomas, pilocytic astrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. FGFR mutations are rarely seen in high-grade gliomas.
Pediatric diffuse astrocytoma and angiocentric glioma typically involve MYB alterations. MYB proteins encode cellular growth and survival. Upregulation of these proteins is consistently found in higher-infiltration-pattern tumors, as previously mentioned.[29]
Adult gliomas are considered among the diffuse gliomas, mainly adult diffuse astrocytoma IDH-mutant and oligodendroglioma (IDH mutant and 1p19q codeletion). Only grade 1 and grade 2 gliomas were originally considered low grade; however, good prognoses in patients with grade 3 gliomas have prompted their integration into a low-grade panorama. Isocitrate dehydrogenase (IDH) presentation is of greater importance for the classification of glial tumors in adults, as an IDH wildtype presentation would automatically classify the tumor as a glioblastoma independently of histological findings. IDH-mutant tumors would be considered within an astrocytoma spectrum.[30] Mutations in IDH carry metabolic consequences in the tumor, increasing its sensitivity to different therapeutic interventions such as chemotherapeutic agents and radiation.
Methylguanine-methyltransferase (MGMT) promoter methylation status is targeted as a potential biomarker for providing information regarding clinical decisions, chemotherapy response, and risk of mutation at recurrence. This marker provide valuable information in high-grade tumors as well as in low-grade gliomas.[31] Previous evidence pointed out the ability to detect MGMT status based on histopathological information in certain tumors such as higher expression Ki-67/MIB-1, increased hypoxia. and decreased angiogenesis. However, more recent evidence suggests no association between histological patterns and MGMT status.[32] Unmethylated MGMT status is a risk factor for poor outcomes in patients with glioblastoma due to its low response to chemotherapeutic agents.
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 codeletion.
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.
Gemistocytic astrocytoma:See Histology
Pediatric diffuse low-grade gliomas
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. Structural alterations of MYB or MYBL1.
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.
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.
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).
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).
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.
Pilomyxoid astrocytoma (WHO grade 1): This tumor is a pilocytic astrocytoma with anaplastic features in histologic analysis.
Pleomorphic xanthoastrocytomas (WHO grade 2):BRAF V600E mutation is characteristic combined with CDKN2A or CDKN2B deletion.
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.
Astroblastoma MN1 altered (grade not established):Tumors with solid and/or cystic components. Perivascular pseudorosettes and MN1 alteration are essential for diagnosis.
Chordoid glioma (WHO grade 2):Well-circumscribed lesion arising in the anterior portion of the third ventricle. Mutations in the PRKCA gene.
The increasing knowledge of these molecular and genetic characteristics opened new research lines to develop drugs towards direct and specific biological targets. Different drugs are being tested and other drugs are already approved for use as targeted therapy in different CNS tumors.
In medically stable patients in whom no inpatient workup is required, follow-up can be done by a neurosurgeon in conjunction with a neurologist and neuro-oncologist. Some lesions might be followed in time without the need for an active acute intervention (eg, tectal gliomas, especially if found incidentally).
Patients who have received some form of treatment (surgery, chemo/radiation therapy) and are medically stable to continue treatment on an outpatient basis will need serial imaging periodically as well as additional forms of therapy like physical and occupational depending on their individual circumstances.
Patients with programmable ventricular shunts should be advised that after every follow-up MRI they should have their shunt settings revised to avoid complications from under or overdrainage of CSF resulting from inadvertent shunt reprogramming.
Inpatient care
The type of treatment as well as the clinical course of each patient will vary depending on the type of tumor and the neurologic status upon admission. Patients with localized lesions in surgically accessible areas and with no neurologic deficits might be scheduled electively. These patients will be admitted to the hospital on the same day of surgery and will typically be discharged three or four days after the procedure. Similarly, patients with unresectable tumors might be admitted for surgical biopsy, which depending on location, can be done using stereotactic techniques. These patients will also be discharged after a few days and depending on the final pathology report will be referred for any additional consults on the outpatient clinic.
Patients who present to the emergency department might require special treatment for the management of related complications like seizures (including status epilepticus) and intracranial hypertension. These conditions might require IV use of antiepileptic medications, intracranial pressure monitoring, external ventricular drain placement, and even emergent surgical resection or decompression in cases of acute herniation. Although low-grade astrocytomas usually present with a more indolent course, some tumors might grow considerably before detection until patients present with acute deterioration or worsening symptoms. In cases like these, patients might require transfer to an intensive care unit for specialized treatment and monitoring.
Transfer
At some institutions, transferring the patient to another facility may be necessary if the proper consultations cannot be obtained. Particularly in patients with significant hydrocephalus, transfer to a facility with neurosurgical coverage is indicated. However, in patients with no hydrocephalus, surgery can be scheduled on an elective but preferably urgent basis.
A presumptive diagnosis of a low-grade glioma can be made from the history, physical, and radiologic appearance of a tumor on CT scan or MRI. The primary care physician should coordinate care with a neurologist, neurosurgeon, and oncologist. The initial treatment steps depend on patient presentation.[33]
One of the classic presenting symptoms in this group of lesions is seizures, which occur in more than 90% of patients. This is more pronounced in oligodendrogliomas but is still very common in low-grade astrocytomas as well.[34] If the patient presents with seizures, first-line therapy is to start the patient on valproic acid, levetiracetam (Keppra), phenytoin (Dilantin), or carbamazepine (Tegretol). Treating the seizures quickly after presentation will reduce the occurrence of seizures in the following 1–2 years after starting the treatment, which does not affect quality of life (QOL) nor results in severe complications as compared to deferred treatment.[35]
If the patient presents with headache and has significant edema surrounding the tumor, dexamethasone (Decadron) therapy is appropriate in doses ranging from 2to 4 mg every 6 hours. With dexamethasone, antiulcer medications (ie, antacids, H2 blockers) usually are prescribed. Corticosteroid therapy may also improve symptoms in patients who have low-grade astrocytomas of the spinal cord. However, treatment with steroids will not solve the primary problem and should be used only for symptom relief, as it is not a definitive treatment of the tumor.
If hydrocephalus is observed on CT scan or MRI and the patient is symptomatic, surgical placement of a ventricular drainage device or an endoscopic third ventriculostomy (ETV) may be appropriate. Either an external ventricular drain or a ventriculoperitoneal shunt may be inserted. The exact procedure depends on any further plans for surgery, with the common agreement to avoid installation of permanent shunts unless there is no other option.
Pharmacotherapy
Trametinib, in combination with dabrafenib, is indicated in pediatric patients aged 1 year and older for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.
Tovorafenib is indicated for relapsed or refractory pediatric LGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation in patients aged 6 months and older.[36]
Aside from the initial measures noted in Medical Care, the cornerstone of therapy for most low-grade gliomas is surgery.[37, 38, 39] Maximum safe resection is the goal of surgical treatment. Positive impact on progression-free survival (PFS), overall survival (OS), and quality of life (QOL) is achieved when complete or even sub-total resections are performed. Residual tumor volume correlates with potential malignant transformation. Hence, multiple reoperations are feasible and sometimes necessary in order to achieve gross total resection (GTR), which is known to correlate with optimal clinical and prognostic results. Nonetheless, even subtotal resection is of benefit if the tumor can be removed safely. Ultimately, histologic diagnosis should be sought for all patients via biopsy or resection if possible.
Tumors in certain locations may be inoperable. Sometimes, with the use of advanced imaging, neuroplasticity is proven (relocation of specific local brain functions), which allows multiple and sequential resections in previously unresectable eloquent areas. The use of intraoperative electrostimulation mapping during surgeries has been shown to maximize safe resection, especially around eloquent areas of the brain. This mapping is useful in understanding the correlation to important white matter fibers (eg, pyramidal tracts), as well as awake craniotomy for cortical mapping of eloquent areas (eg, speech-related areas), which provides higher extent of resection and less permanent postoperative deficits.
Surgery is also the primary mode of treatment for low-grade astrocytomas of the spinal cord. Depending on the appearance of the tumor at surgery, a gross total resection, subtotal resection, or only biopsy may be possible. However, resection may lead to symptomatic and objective improvement in these patients. Furthermore, in low-grade astrocytomas, long-term readmission (> 10 y) and even cure are frequent in both children and adults.
The extent of resection is measured differently for high-grade glioma, low-grade glioma, and pediatric gliomas. For classic enhancing tumors (high-grade gliomas and some of the pediatric gliomas like pilocytic astrocytomas) the extent of resection is determined by the remnant of enhancing tumor left after resection. For low-grade nonenhancing gliomas, like diffuse low-grade astrocytoma, the identification of the tumor volume relies primarily on the identification of T2/FLAIR abnormalities.[40, 41] As a result, gross total resection (GTR), defined as the complete radiographic resection of regions of T2/FLAIR hyperintensity in nonenhancing lesions.
Intraoperative 5-ALA fluorescence can be used to help achieve a greater extent of resection.[42] Fluorescence-guided resection has shown great potential for maximizing EOR because it permits real-time intraoperative identification of residual tumor tissue.[40] Preoperative administration of 5-ALA results in preferential accumulation of fluorescent protoporphyrin IX (PpIX) in malignant tissues compared with normal brain.[40] A study published by Sanai et al[43] showed that intraoperative confocal microscopy can help visualize cellular 5-ALA–induced tumor fluorescence within low-grade gliomas and at the brain-tumor interface.
The use of intraoperative imaging to guide the resection of gliomas in general has provided surgeons with a new tool to improve the extent of resection.[44] Today, two important tools are the intraoperative ultrasound (iUS) and intraoperative MRI (iMRI). iUS offers valuable real-time information about the location, size, vascular relationships, and adjacent structures of brain tumors.[45, 46] In some systems, there is a way to incorporate iUS with preoperative imaging (merging real-time iUS imaging with the navigation imaging), so the surgeon can evaluate how much he took out and identify tumor margins that were left behind.[45, 46, 47] iMRI is a more complex solution that can provide real-time imaging and is important especially with low-grade astrocytomas when it is hard to understand tumor margins from surrounding healthy brain tissue. One problem with this technology is its high cost and limited availability. It also extends operating times, which could be a downside for patients with high anesthetic risk.
Intraoperative neurophysiological monitoring has been used increasingly in the last few years.[48, 49] (See Intraoperative Neurophysiological Monitoring.) This is a preferred technique to remove lesions close to, or involving, eloquent (functionally important) regions of the brain. The goal of such monitoring is to identify changes in brain and spinal cord function prior to irreversible damage. Intraoperative monitoring also has been effective in localizing anatomical structures, which helps guide the surgeon during dissection.
Awake craniotomy
One of the electrophysiological modalities is intraoperative cortical mapping, which can help to achieve a greater extent of resection. This technique is often used in combination with awake craniotomy, which is commonly employed for tumors invading eloquent areas of the brain to achieve maximum safe resection of the tumor. In awake craniotomy, the patient is awake during parts of the procedure. With the patient awake, it is possible to test regions of the brain before they are incised or removed, and patient’s function is tested continuously throughout the operation. The mapping is often done with small electrodes that stimulate certain areas of the brain and evoke particular responses.
Awake craniotomy can reduce the rate of recurrence through the achievement of radical resection of the lesion, preserving functional outcomes; however, bigger tumors with higher degrees of invasion can preclude safe resection. The prehabilitation of cortical areas through the catalyzation of cortical plasticity has been described in adult cohorts for gliomas WHO grades 2 and 3. This intervention allows a greater extent of resection while preserving function and improving survival.[50] Pediatric cohorts have not been described.
Intraoperative MRI (IoMRI) can be implemented in awake craniotomy procedures. During resection, a shift in the brain and navigation of the preoperative MRI occurs due to the surgical manipulation of the parenchyma. IoMRI can compensate for this setback and provide useful real-time information to the surgeon.[51]
Awake craniotomy can be a feasible option in pediatric patients, with cohorts demonstrating good functional outcomes and the achievement of radical resection of the lesions. The first meta-analysis of this subject concluded the feasibility of performing awake craniotomy in pediatric patients; nonetheless, literature remains scarce compared to adult studies, and an emergence of new literature can be expected in the forthcoming years.[52] Despite this, awake craniotomy presents some setbacks in children compared to their adult counterparts. Poor cooperation in patients younger than 10 years old summed up to functional and anatomical differences considerably reduce the number of pediatric candidates for these procedures.[53]
See Brain Cancer Treatment Protocols for summarized information.
Laser Interstitial Thermal Therapy (LITT)
Tumors in deep areas or inaccessible regions of the brain due to a close relation to vital structures may preclude surgical or radiation treatment. LITT is a minimally invasive technique with thermal ablation of specific lesions that cannot be treated through surgery or radiation, which are their most common indication for this procedure. This technique can be used with conjoined employment of imaging techniques that allow a real-time evaluation of ablation extent.[54]
The most reported complications associated with LITT therapy are new neurological deficit and edema; however, other complications related to this procedure include hemorrhage, seizures, hydrocephalus, and wound infection. Complication rates are reported to reach up to 31% of cases. Evidence regarding safety and long-term survival of patients remains limited. In the most recent clinical series evaluating overall survival of patients with low-grade astrocytomas treated with LITT was of 50 months after the procedure.[55] The employment of this procedure should be reserved for inaccessible lesions through a conventional surgical approach or if there are contraindications for radiation therapy. Also, patients with failed previous surgical resections may be candidates for LITT.
Focused ultrasound (FU)
Focused ultrasound (FU) can be utilized to treat tumors categorized as inoperable due to near relation to vital anatomic structures in the brain with reduced rates of blood loss and risk of infection. However, in recent years, an increasing interest has emerged regarding the use of focused ultrasound to disrupt the blood–brain barrier to allow the delivery of medications to the brain, with promising results continuously published. Research regarding this therapy extends from delivering chemotherapeutic agents in brain tumors to degenerative diseases such as Alzheimer's with the delivery of monoclonal antibodies for reduction of amyloid in the brain.[56, 57] This is allowed by intensity modalities in this therapy. High-intensity FUS (HIFU) creates high levels of thermal energy, prompting cell death. Its low-intensity counterpart (LIFU) is used simultaneously with the injection of microbubbles that facilitate mechanical and molecular disruption of the blood–brain barrier due to the bubbles' gas oscillation, enabling increased delivery of pharmacological agents.[58]
Studies in rodent models have demonstrated an increase in delivery of pharmacological agents to the brain ranging from 2.7-fold to 3.9-fold higher than that in control groups.[57] Human trials remain scarce; nevertheless, optimal results have been demonstrated.
Spinal surgery
In spinal surgeries for resection of low-grade astrocytomas, monitoring usually includes sensory-evoked potentials, motor-evoked potentials, and the use of direct waves (D-waves), which allows for monitoring the propagation of cortical stimulation along the white matter fibers of the spinal cord.
Patients in whom a low-grade astrocytoma is suspected should be evaluated primarily by a neurosurgeon. The best treatment involves a multidisciplinary approach with a team made up of a neurosurgeon, neuro-oncologist, neuropathologist, neurologist, neuropsychologist, and neuroradiologist. The neurosurgeon will guide the diagnostic evaluation, preferably after maximally safe resection of the tumor. After surgery the team will decide on the best approach to treat the patient; either continue followup only (eg, after GTR of pilocytic astrocytoma), adjuvant oncological treatment, and sometimes additional surgery for tumor remnants.
Patients who present with seizures will usually receive initial treatment from a neurosurgeon. Further treatment and the decision of weaning the patient off of antiepileptic drugs is usually managed by a neurologist.
Other consultations should be considered only in individual circumstances (eg, psychiatry in patients with concomitant psychoaffective disorders).
There are no special dietary restrictions for patients with brain tumors, although patients with pre-existing medical conditions that warrant dietary modifications must continue to abide by their previous regimens to avoid potential complications (eg, episodes of hypo/hyperglycemia in diabetic patients).
In general, no restrictions are placed on activity of patients with low-grade glioma. However, patients' activity may relate to their overall neurologic status. The presence of seizures may prevent the patient from driving. Neurologic deficits such as hemiparesis may improve after treatment. Physical therapy is often beneficial.
Adjuvant therapy is usually recommended in glioma patients presenting with bad prognostic factors. Table 3 summarizes these factors. Many of these factors are also predictive of poor response to treatment. Currently, there is a lack prospective studies that reveal the long-term benefit in overall survival and quality of life as result of adjuvant treatment. There is also a lack of data regarding the change in the cognitive and neuropsychological status of the patient as a result of adjuvant treatment. Another unsolved issue is recurrent disease. Some advocate repeating surgery before changing the oncologic regimen. Others choose the treatment in relation to risk factors; low-risk patients will be sent for surgery and then possible radiotherapy, while high-risk patients that initially were treated with radiotherapy and chemotherapy are ultimately rescued with other chemotherapy regimens with or without repeat resection.[59, 60]
The results from the RTOG 9802 randomized trial[59, 61] showed that low-risk, low-grade glioma patients (those who had complete resection by postoperative imaging and were younger than 40 years old) exhibited a 93% five-year survival rate and a 48% five-year progression-free survival (PFS) rate without any adjuvant therapy. These results were very similar to those obtained by another important trial, EORTC 22845, which tested patients for postoperative radiotherapy alone (either immediately after surgery or in progression) and found a five-year PFS rate of 44% in the group that received immediate post-surgical radiation therapy.
One important unsettled debate regarding the routine use of radiotherapy is the fact that most patients with low-grade gliomas are young and survive longer, and thus, they may show more than usual cognitive deterioration related to radiation therapy focused on the brain. As a result, today's paradigm is to treat with radiotherapy patients that have the highest probability of progression (age older than 40 years, preoperative tumor size larger than 5 cm, partial resection, astrocytic histology, lack of co-deletion and lack of IDH mutation) or had progressed after good resection and chemotherapy.[9]
For high-risk patients, the addition of PCV to radiation therapy markedly improves PFS, doubles OS, and seems to preserve cognitive function.[59] The use of temozolomide (alone or concomitant) instead or before PCV is still under investigation, but it seems at least comparable in terms of QOL and survival; it has already became the standard of care in some centers that prefer its less toxic side effects.
In the pediatric population, children have excellent outcomes with prolonged survival, especially when a gross total resection (GTR) of the tumor is achieved. Yet, in cases where subtotal resection is achieved, or when resection is not possible, but biopsy is, sometimes there is a need for multiple treatment regimens to halt progression of tumor growth.[13, 62, 63] Pediatric low-grade gliomas differ considerably from adult presentations, as does prognosis. Certainly, adult tumors tend to have a poorer prognosis compared to their pediatric counterparts due to the increased risk of undergoing malignant transformation. Therefore, adjuvant therapy in the pediatric population can be considered undesirable. Radiotherapy in younger populations has shifted from standard therapy to an undesirable option because of the increased long-term consequences of radiotherapy in this population. Different chemotherapeutic regimens can be offered to delay or outright avoid radiotherapy.
Mortality in children tends to occur either from tumor-related morbidity (tumor progression, malignant transformation) or toxicity-related morbidity from the treatments. Tumor progression in the pediatric population sometimes relates to the fact that the anatomical location tends to be different from their adult counterpart, with more deep-seated midline location like thalamic tumors, brainstem tumors, and so on. In recent years, these tumors were found to harbor H3K27M and MAPK pathway mutations, which are known today to be bad prognostic factors with biological behavior of high-grade tumors rather than low-grade tumors. This understanding shifts the treatment paradigm toward more active and aggressive measures.
Targeted therapy
In recent years, much data has been published on molecular biology and genomics of low-grade gliomas in the adult as well as pediatric population. Aberrant signaling in pathways like RAS/MAPK or the PI3K/Akt/mTOR network have been identified in low-grade gliomas, and clinical trials are ongoing to target this pathway as a therapeutic approach.[64] In addition, ongoing studies are evaluating inhibitors of IDH.[65] The ability to image levels of the oncometabolite 2-hydroxyglutarate is an exciting area of research to develop noninvasive robust biomarkers of treatment response and clinical outcome in IDH-mutated tumors.[66] BRAF V600E mutations are found in pediatric low-grade gliomas and in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E–GBM), a rare variant of GBM.[67]
Pilocytic astrocytomas can exhibit different alterations such as mutations or translocations in BRAF, MAPK, NF-1, RAF, etc. Different trials are currently addressing these markers for targeted therapy. Monoclonal antibodies such as selumetinib for MERK (MAPK/ERK kinase) inhibition or dabrafenib and trametinib directing BRAF V600E mutations are currently used to target tumors with these characteristics, showing successful response in patients. In tumors that harbor the V600E mutation, treatment with BRAF inhibitors was shown to result in significant cytoreduction while under treatment. In the pediatric population, it was shown that when the V600E mutation is present, treatment with conventional chemotherapy leads to worse prognosis in comparison to BRAF inhibitors.[68] Similarly, diffuse astrocytomas can receive adjuvant therapy with conventional chemotherapy and radiotherapy as well as MEK inhibitors (selumetinib).
Everolimus can be employed in patients with mTOR hyperactivation with full-dose treatment followeed by low-dose regimens for maintenance. Everolimus is FDA-approved for the treatment of subependymal giant cell astrocytomas (SEGAs).[69]
Comparisons between chemotherapeutic agents and targeted therapies with monoclonal antibodies are currently undergoing clinical trials by the Children's Oncology Group in patients with low-grade gliomas associated with NF-1 as well as low-grade gliomas with no association with NF-1.
Similarly, a protocol carried out at St. Jude Children's Research Hospital is assessing the efficacy of mirdametinib (MEK inhibitor) in patients with pediatric low-grade glioma. This protocol is divided into two phases and estimated to be completed by 2031. The first phase of the protocol looks to estimate the maximum tolerated dose for these patients as well as the safety and tolerability of the drug. In the second phase, patients will be divided into 3 different cohorts evaluating patients with newly diagnosed low-grade glioma, progressive or recurrent low-grade glioma without previous treatment of MEK inhibitors, and progressive or recurrent low-grade glioma previously treated with MEK inhibitors. The most common side effects associated with mirdametinib are rash, diarrhea, and vomiting in the pediatric population, and rash, diarrhea, and nausea in adults.
A clinical trial carried out at the Children´s Hospital in Los Angeles, CA tested the drug binimetinib (MEK inhibitor) in children with low-grade glioma. Participants received the drug orally twice daily for up to 2 years. The main goals of the protocol are to assess the effective non-toxic dose of the drug as well as its efficacy in children with low-grade glioma. Results are not yet available, however, the primary completion date was updated in November 2022. Binimetinib (Mektovi) has shown efficacy in different types of cancers with BRAF mutations, such as melanoma and non-small-cell lung cancer.
inimetinib can be associated with certain side effects as fatigue, nausea, diarrhea, vomiting, abdominal pain, constipation, dizziness, bleeding (GI bleed, hematomas, bleeding gums), and blurred vision,
CAR-T cells
Genetically engineered T cells adapted to express chimeric antigen receptors (CAR) have shown unprecedented results in different malignancies, especially those of hematologic etiology. The main goal of this therapy is to induce a cellular response through T or NK cells to tumoral cells expressing a specific antigen sparing normal brain cells.
Research for CAR T-cell therapy has increased due to the poor prognosis glioma patients face. However, even though potential targets (HER2, IL-13Rα2HER2, IL-13Rα2, EGFRvIII) have demonstrated to induce response, their expression in these tumors is inconstant and at undesired levels to be considered as a standard therapy target. In contrast, B7H3 (transmembrane protein) is expressed widely in different solid tumors. Also, B7H3 has shown to be expressed on tumoral glioma tissue of different WHO grades but not in adjacent normal brain tissue. [70] However, there is scarce literature on using CAR T cells in pediatric patients. The limited understanding of CAR in pediatric populations, in addition to possible multifactorial causes, limits the efficacy of these therapies in pediatric brain tumors. Reported CAR targets in pediatric tumors are HER2, IL-13Rα2, EphA2, B7-H3, EGFRvIII, TNC, and GD2. Studies strongly support preclinical trials of CAR T-cell therapy for pediatric brain tumors. Results show strong antitumor activity with B7-H3 CAR T cells in orthotopic models.[71]
Different setbacks are poised to be addressed, as the microenvironment of many gliomas is not fully understand. Evidence addresses this problem, looking to elucidate the precise mechanisms that convey resistance to immunotherapy.[72] Hatae et al published their work with CAR T cells enhanced with metformin (AMPK activator) and rapamycin (mTOR inhibitor) to overcome hypoxic conditions typically encountered in the microenvironment of gliomas. Results of their work demonstrated optimal functionality of human CAR-T cells in in vitro hypoxic conditions, opening the possibility of performing human trials with this method.[73]
Dabrafenib (Tafinlar), in combination with trametinib (Mekinist), is indicated in pediatric patients aged 1 year and older for low-grade glioma with a BRAF V600E mutation who require systemic therapy. Approval was based on results from the phase 2/3 TADPOLE trial that showed patients randomized to receive dabrafenib plus trametinib experienced a statistically significant improvement in overall response rate (ORR) of 47% (CI: 35-59%) compared with 11% who were randomized to receive chemotherapy. At a median followup of 18.9 months, median progression-free survival (PFS) was 20.1 months with the immunotherapy combination compared with 7.4 months with chemotherapy (P < 0.001).[74]
Tovorafenib is indicated for relapsed or refractory pediatric LGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation, in patients aged 6 months and older.[36]
Additionally, certain conditions (in the setting of low-grade astrocytoma) typically require treatment with antiepileptic drugs, steroids, etc.
Clinical Context:
Dabrafenib, in combination with trametinib, is indicated in pediatric patients aged 1 year and older for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.
Clinical Context:
Indicated for relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation, in patients aged 6 months and older.
BRAF V600E mutations activate the BRAF pathway, which includes MEK1 and MEK2. Mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 and activation of MEK1 and MEK2 kinase in signal-related kinase (ERK) pathway promotes cellular proliferation. Inhibiting this pathway decreases tumor growth.
Clinical Context:
Trametinib, in combination with dabrafenib, is indicated in pediatric patients aged 1 year and older for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.
Mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 and activation of MEK1 and MEK2 kinase in signal-related kinase (ERK) pathway promotes cellular proliferation. Inhibiting this pathway decreases tumor growth.
Clinical Context:
In general, acts to block sodium channels and prolongs refractory period of nerve impulses. As such, is a very effective anticonvulsant. First-line drug in partial and generalized tonic-clonic seizures.
Clinical Context:
Like phenytoin, acts by limiting influx of sodium ions across sodium channels and blocking repetitive neuronal firing. First-line drug in partial seizures and may be used for tonic-clonic seizures as well. Serum levels should be checked.
Clinical Context:
Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is through modulation of neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain.
Clinical Context:
Postulated mechanisms of action of corticosteroids in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.
Clinical Context:
Everolimus can be employed in patients with mTOR hyperactivation with full-dose treatment followed by low-dose regimens for maintenance. FDA-approved for the treatment of subependymal giant cell astrocytoma (SEGA)
Omar R Ortega-Ruiz, MD, Research at Deparment of Neurosurgery, Hospital Zambrano Hellion, San Pedro Garza García, Nuevo León, México
Disclosure: Nothing to disclose.
Coauthor(s)
George I Jallo, MD, Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine
Disclosure: Nothing to disclose.
Meleine M Martinez-Sosa, MD, Resident Physician, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine
Disclosure: Nothing to disclose.
Nir Shimony, MD, Assistant Professor of Neurological Surgery, Division of Pediatric Neurosurgery, Department of Surgery, St Jude Children’s Research Hospital, Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Baptist Children’s Hospital, and Semmes Murphey Clinic, University of Tennessee Health Science Center College of Medicine; Adjunct Faculty, Department of Neurosurgery, Johns Hopkins University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Jorge C Kattah, MD, Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Disclosure: Nothing to disclose.
Chief Editor
Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
David A Chesler, MD, PhD, Clinical Assistant Professor of Neurological Surgery and Pediatrics, Stony Brook University Hospital; Co-Director of Pediatric Neurosurgery, New York Spine and Brain Surgery, UFPC
Disclosure: Nothing to disclose.
Eveline Teresa Hidalgo , MD, Surgeon, Division of Pediatric Neurosurgery, Department of Neurosurgery, NYU Langone Medical Center
Disclosure: Nothing to disclose.
Rafael Uribe-Cardenas, MD, Resident Physician in Neurosurgery, Department of Neuroscience, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Colombia
Disclosure: Nothing to disclose.
Rodrigo O Kuljis, MD, Esther Lichtenstein Professor of Psychiatry and Neurology, Director, Division of Cognitive and Behavioral Neurology, Department of Neurology, University of Miami School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Ethan A Benardete, MD, PhD Staff Physician, Department of Neurosurgery, New York University Medical Center
Disclosure: Nothing to disclose.
References
WHO Classification of Tumours Editorial Boards. Gliomas, glioneuronal tumours,and neuronal tumours. WHO Classification of Tumours Editorial Board. Central nervous System tumours. Fifth edition. Lyon: International Agency for Research on Cancer; 2021. 6: 15-186.
Quinn T Ostrom, Mackenzie Price, Corey Neff, Gino Cioffi, Kristin A Waite, Carol Kruchko, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016–2020. Neuro-Oncology. ISSN 1522-8517: Oxford University Press; October 2023. 25: iv1–iv99.
Julius Griauzde, Ahmad Khaldi, Edward Melian, Ricarchito Manera, Margaret Primeau, Darrin M. Aase, et al. Pilocytic Astrocytojma: A Comprehensive Review. Contemporary Neurosurgery. June 30, 2011. 33:1-6.
P. Kleihues, D.N. Louis, O.D. Wiestler, P.C. Burger, B.W. Scheithauer. WHO grading of tumours of the central nervous system. David N. Louis, Hiroko Ohgaki, Otmar D. Wiestler, Webster K. Cavenee. WHO Classification of Tumours of the Central Nervous System. 4th. International Agency for Research on Cancer (IARC); 2007. 10.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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