Low-Grade Astrocytoma 

Updated: Dec 21, 2017
Author: George I Jallo, MD; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS 

Overview

Background

Low-grade astrocytomas are a heterogeneous group of intrinsic central nervous system (CNS) neoplasms that share certain similarities in their clinical presentation, radiologic appearance, prognosis, and treatment. The most common intrinsic brain tumor, glioblastoma multiforme, is high grade and malignant. This contrasts with low-grade astrocytomas, which are less common and therefore less familiar to practitioners.

Improvements in neuroimaging permit the diagnosis of many low-grade astrocytomas that would not have been recognized previously. Low-grade astrocytomas are, by definition, slow growing, and patients survive much longer than those with high-grade gliomas. Proper management involves recognition, treatment of symptoms (eg, seizures), and surgery, with or without adjunctive therapy. Low-grade astrocytomas are found along the central nervous system (brain and spinal cord). In the past few years, new observations concerning molecular precursors and molecular diagnostics in adult and pediatric populations with low-grade gliomas have yielded a change in the pathological classification of all gliomas including astrocytomas (eg, World Health Organization [WHO] classification[35] ).

Pathophysiology

Low-grade astrocytomas are primary tumors (rather than extraaxial or metastatic tumors) of the brain. Astrocytomas are one type of glioma, a tumor that forms from neoplastic transformation of the so-called supporting cells of the brain, the glia or neuroglia. Gliomas arise from the glial cell lineage from which astrocytes, oligodendrocytes, and ependymal cells originate. The corresponding tumors are astrocytomas, oligodendrogliomas, and ependymomas. Grading of a glioma is based on the histopathologic evaluation of surgical specimens. The old World Health Organization (WHO) scheme was based on the appearance of certain characteristics only: atypia, mitoses, endothelial proliferation, and necrosis. These features reflect the malignant potential of the tumor in terms of invasion and growth rate. Tumors without any of these features were classified as grade I. Tumors with cytological atypia alone were considered grade II (diffuse astrocytoma). Those that show anaplasia and mitotic activity in addition to cytological atypia were considered grade III (anaplastic astrocytoma) and those exhibiting all of the previous features as well as microvascular proliferation and/or necrosis were considered grade IV.[1]

In the last few years, as mentioned, a great shift in our understanding of these tumors occurred and the standard diagnostic evaluation of gliomas must now include a molecular assessment of isocitrate dehydrogenase (IDH) mutations and codeletion of chromosome arms 1p and 19q to be considered complete.[38, 39, 40, 41, 42] In fact, today we know that these molecular diagnostic markers are crucial for our primary classification, which should be based primarily on mutational status, rather than solely on histological grade.[35] Two phase III trials have indicated that although initial treatment with either chemotherapy or radiation therapy might produce similar results overall, outcomes vary by molecular diagnosis.[69]  These new molecular and genetic parameters are now integrated in our decision-making paradigm regarding diagnosis, prognosis, and treatment. Prognosis is more closely associated to the molecular fingerprinting than to morphology and histology, however, the previous grade classification remains relevant as well. Immunohistochemistry and cytogenetics provide an accurate diagnosis for most patients, whereas chromosomal and gene arrays provide more complete diagnostic information for some tumors.[38]   

Another important distinction is between pediatric and adult low-grade astrocytomas. Pediatric low-grade astrocytomas exhibit markedly different molecular alterations, clinical course, and treatment than their adult counterpart.

Grades I and II astrocytomas comprise the low-grade group of astrocytomas.

A subset of low-grade astrocytomas may have features of high-grade lesions including endothelial proliferation and necrosis, although they remain slow growing and well circumscribed. This subset comprises juvenile pilocytic astrocytoma (JPA), pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma (PXA), and subependymal giant-cell astrocytoma (SEGA).

Low-grade astrocytomas generally cause symptoms by perturbing cerebral function (i.e. seizures), elevating intracranial pressure (ICP) by either mass effect or obstruction of cerebrospinal fluid (CSF) pathways (i.e. hydrocephalus), causing neurologic deficits (i.e. paralysis, sensory deficits, aberrant behavior), headaches and endocrine abnormalities.

Most low-grade astrocytomas tend to occur in the lobes of the cerebral hemispheres. Although pilocytic astrocytomas can occur supratentorially, the cerebellum is their most common location especially in children. Pleomorphic xanthoastrocytomas (PXA) are more common in the supratentorial space in a characteristic superficial location, which involves both the cerebrum as well as the overlying meninges. Subependymal giant-cell astrocytomas (SEGA) are found most commonly in the wall of the lateral ventricles and are associated with tuberous sclerosis, an autosomal dominant disease that causes growth of benign tumors in different organ systems.

The main group of low-grade astrocytomas are diffuse astrocytomas. One of the important features to differentiate diffuse astrocytomas from oligodendrogliomas is the lack of 1p/19q co-deletion. The latest 2016 WHO classification is based on molecular subtyping:

  • Diffuse astrocytoma, IDH-mutant (WHO grade II) is described as a diffusely infiltrating astrocytoma with a mutation in either the IDH1 or IDH2 gene. The histology of this type of tumor is typically composed of cells with moderate pleomorphism, and shows advanced astrocytic differentiation. It has a relatively slow growth pattern. Other important stains that support the diagnosis are the presence of TP53 and ATRX mutations.
  • Gemistocytic astrocytoma, IDH-mutant (WHO grade II) remains the only histopathologically defined subtype of astrocytoma, and accounts for ~10% of WHO grade II diffuse astrocytomas. This histological subtype is known for being described as having a higher tendency for malignant transformation, however, it is not yet known what the risk in correlation to IDH mutation is.
  • Diffuse astrocytoma, IDH-wild-type  is a diffusely infiltrating astrocytoma without mutations in the IDH genes. This diagnosis is rare and likely to change in the next release of the WHO classification. This specific subtype harbors a variety of tumors that can be again reclassified by future genetic and molecular studies. [39, 40]
  • Diffuse astrocytoma, NOS is a tumor with histopathological features of a diffuse astrocytoma in which IDH mutation status has not been fully assessed (ie, not tested, lost, not known, etc.). The WHO states the use of this subgroup should be minimal and promotes its disuse.
  • Midline diffuse low-grade gliomas should be distinguished from regular diffuse astrocytomas by mutation in histone H3 (Lys27Met mutation). Histological grade does not predict the outcome of the highly aggressive tumors with this mutation.
  • Others  is a group that includes pilocytic astrocytoma, pleomorphic xanthastrocytoma, and subependymal giant cell astrocytoma. In the latest classification, some tumors that were once known as different sub-groups, for example, diffuse astrocytomas and oligodendrogliomas, were reorganized under the same subtype (diffuse astrocytoma depends on the IDH mutation status). On the other hand, a more obvious differentiation has been established between some tumors that were once thought to be of similar subtypes like diffuse astrocytomas and pilocytic astrocytomas. This classification leaves those astrocytomas that have a more circumscribed appearance, lack IDH gene family mutations, and frequently have BRAF mutations (pilocytic astrocytoma, pleomorphic xanthastrocytoma) or TSC1/TSC2 mutations (subependymal giant cell astrocytoma) distinct from the diffuse gliomas. [35]

Epidemiology

Frequency

United States

The overall incidence of all primary malignant and non-malignant brain and other CNS tumors is 22.36 cases per 100,000 people (7.18 per 100,000 for malignant tumors and 15.18 per 100,000 for non-malignant tumors for a total count of 250,211 incident).[37] In children, the rate of primary malignant and non-malignant tumors is 5.67 per 100,000. Of all glioma subtypes, diffuse astrocytomas represent 9.1% and pilocytic astrocytomas 5.1%.[2] These numbers are derived from the prior classification system and do not reflect the latest changes in the system. Although these numbers represent an approximate estimation of the epidemiology of low-grade astrocytomas, it is important to note that there are no studies that have addressed this group in an isolated fashion. This is in part due to the fact that low-grade astrocytomas are generally categorized as part of a broader group collectively known as low-grade gliomas which include tumors derived from oligodendrocytes as well as mixed glial-neuronal tumors.

Gliomas are associated with certain phakomatoses, especially neurofibromatosis type 1 (NF-1). Low-grade astrocytomas occur more commonly in these patients, particularly in the optic nerves and optic chiasm. As mentioned before, subependymal giant-cell astrocytomas are found almost exclusively in patients with tuberous sclerosis.

International

The incidence of low-grade astrocytomas has not been shown to vary significantly by nationality. However, studies examining the incidence of malignant CNS tumors have shown some differences based on nationality. Since some high-grade lesions arise from low-grade tumors, these trends are worth mentioning. Specifically, the incidence of CNS tumors in the United States, Israel, and the Nordic countries is relatively high, while Japan and other Asian countries have a lower incidence. These differences probably reflect some biological disparities, as well as discrepancies in pathologic diagnosis and reporting.

A study of the incidence of brain tumors in Europe concluded that of all glial tumors, the astrocytic subtype is the most common with a reported incidence of 4.8 cases per 100,000 people per year. This number represents all astrocytic tumors without a specific mention of low-grade cases.[3]

 

Mortality/Morbidity

Due to the inherent differences in biology and natural history of this heterogeneous patient population, it is difficult to determine an exact mortality rate for low-grade astrocytomas. The update in classification and the new molecular subtyping (ie, change of the once called diffuse pontine glioma with midline glioma) stress the need for new studies and statistics focusing on the different subtypes.

Pilocytic tumors can potentially be cured with surgical resection, and in specific cases where resection is not amenable, these can be treated with BRAF inhibitors.[43] Pilocytic astrocytomas have a 25-year survival rate of 95% when they are cystic and well circumscribed. For cerebellar tumors that are completely resected, the 10-year survival rate is almost 100%.[4] Although survival is affected by some prognostic factors, average overall survival from diagnosis is about 5–6 years, ranging from 3 to 10 years. Based on these numbers, these tumors should not be considered benign tumors, but a chronic disease state that continually invades and compromises the brain until a potential malignant transformation occurs.[44]

Race

No clear evidence has been published that low-grade astrocytomas are more common in any racial or ethnic group. In the United States, malignant CNS tumors are slightly more common in whites than in blacks. Whether this applies to low-grade tumors remains to be studied.

Sex

There is a slight female predominance in the incidence of primary brain and CNS tumors according to the latest report of the Central Brain Tumor Registry of the United States (CBTRUS). The rate is higher in females (24.46 per 100,000 tumors) than in males (20.10 per 100,000 tumors).[37, 2]

Age

The median age of patients diagnosed with a low-grade astrocytoma is approximately 35 years old, which is a younger age than that of patients with malignant gliomas. Juvenile pilocytic astrocytomas have a median age at diagnosis that is about a decade younger than other low-grade astrocytomas. The incidence of primary brain tumors, malignant astrocytomas in particular, is increasing in elderly patients.[5] Whether this is a true increase in incidence or simply the result of higher rates of detection due to increased imaging or reporting is unknown.

 

Presentation

History

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.[6] 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 this 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.[45, 44, 46] 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. 

Physical

A comprehensive neurological exam must be performed on any patient who is suspected of harboring an intracranial lesion. In most centers specialized in neurooncology, it is common to use the Karnofsky Performance Score (KPS) in order 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.

Causes

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.[7]

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.

 

DDx

 

Workup

Laboratory Studies

No specific laboratory test is available for the diagnosis or follow-up of low-grade gliomas. There are promising studies, which aim to detect circulating tumor DNA in human malignancies. Although this technology hasn't been applied to low-grade gliomas yet, it could potentially be implemented in the future as a screening, diagnostic and/or follow-up tool.[8]

 

Imaging Studies

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.

A 28-year-old male taxi driver presented to the em 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.

Magnetic resonance imaging

On MRI, low-grade astrocytomas show decreased signal relative to surrounding brain on T1 sequences (see following images).

Preoperative MRI of the brain of a 28-year-old mal 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 l 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 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 juveni 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. 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.

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.

T2-weighted sequences of an MRI of the brain of a 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 grad 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.

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 follow-up of low-grade gliomas with high sensitivity for tumor recurrence.[70]

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.

Other Tests

See the list below:

  • 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.
  • Neuropsychology evaluation is important and can help to evaluate pre- and postoperative function. Subtle changes in repeated neuropsychology testing has been shown to correlate with tumor progression.

Procedures

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.

Histologic Findings

The histologic findings in low-grade astrocytomas vary according to the specific tumor type. As reviewed before, these lack high-grade features like necrosis, microvascular proliferation, and high mitotic indices.

Pilocytic astrocytomas show the presence of bipolar piloid cells with long hair-like processes and Rosenthal fibers. Pilomyxoid astrocytomas are dominated by the presence of a mucoid matrix, monomorphous bipolar cells and an angiocentric cell arrangement. Pleomorphic xanthoastrocytomas have a variable histological appearance, hence the name. The term xanthoastrocytoma is derived from the presence of xanthomatous cells, which show intracellular accumulation of lipids. Diffuse astrocytomas are composed of well differentiated fibrillary or gemistocytic neoplastic astrocytes on the background of a loosely structured microcystic tumor matrix.[1]

 

Staging

There are currently no valid staging systems in clinical use.

 

Treatment

Medical Care

From the history, physical, and radiologic appearance of a tumor on CT scan or MRI, a presumptive diagnosis of a low-grade glioma can be made. The primary care physician should coordinate care with a neurologist, neurosurgeon, and oncologist. The initial treatment steps depend on patient presentation.[9]

One of the classic presenting symptoms in this group of lesions is seizures, as mentioned before. Seizures occur in more than 90% of patients. This is more pronounced in oligodendrogliomas, but still very common in low grade astrocytomas as well.[47] 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 QOL (quality of life) nor results in severe complications, as compared to deferred treatment.[48]

If the patient presents with headache and has significant edema surrounding the tumor, dexamethasone (Decadron) therapy is appropriate in doses ranging from 2-4 mg every 6 hours. With dexamethasone, antiulcer medications (ie, antacid, H2 blocker) 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.

Surgical Care

Aside from the initial measures noted in Medical Care, the cornerstone of therapy for most low-grade gliomas is surgery.[10, 11, 12] Maximum safe resection is the goal of surgical treatment. Positive impact on PFS (progression-free survival), OS (overall survival) and QOL (quality of life) 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, which is known to correlate with best 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) 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 non-enhancing gliomas, like diffuse low-grade astrocytoma, the identification of the tumor volume relies primarily on the identification of T2/ FLAIR abnormalities.[49, 51] 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.[52] Fluorescence-guided resection has shown great potential for maximizing EOR because it permits real-time intraoperative identification of residual tumor tissue.[49] Preoperative administration of 5-ALA results in preferential accumulation of fluorescent protoporphyrin IX (PpIX) in malignant tissues compared with normal brain.[49] A study published by Sanai et al[13] 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.[14] 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.[53, 54] 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.[53, 54, 55] 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.[15, 16] (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.

One of the electrophysiological modalities is intraoperative cortical mapping, which can help to achieve a greater extent of resection. The mapping is often done with small electrodes that stimulate certain areas of the brain and evoke particular responses. This technique is often used in combination with awake craniotomy.

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.

See Brain Cancer Treatment Protocols for summarized information.

In spinal surgeries for resection of low-grade astrocytomas, the monitoring usually includes sensory-evoked potentials, motor-evoked potentials, and the use of direct wave (D-waves), which allows for monitoring the propagation of cortical stimulation along the white matter fibers of the spinal cord.

Consultations

Patients in whom a low-grade astrocytoma is suspected should be evaluated primarily by a neurosurgeon. The best treatment modality is through a multidiscipline approach with a team structured with neurosurgeon, neurooncologist, neuropathology, neurologist, neuropsychology, and neuroradiology. 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 follow-up only (eg, after GTR of pilocytic astrocytoma), adjuvant oncological treatment, and sometimes re-do surgery for tumor remnant.

Patients who present with seizures usually will receive first treatment by the neurosurgeon. Further treatment and the decision of weaning the antiepileptic drugs usually will be managed by a neurologist.

Other consults should be considered only in individual circumstances (eg, psychiatry in patients with concomitant psychoaffective disorders).

Diet

There are no special dietary restrictions for patients with brain tumors although patients with pre-existing medical conditions which warrant dietary modifications must continue to abide by their previous regimens to avoid potential complications (e.g. episodes of hypo/hyperglicemia in diabetic patients).

Activity

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.

Role of Adjuvant Therapy

Adjuvant therapy is usually recommended in patients presenting with bad prognostic factors. These factors are summarized in Table 3. Many of these factors are also predictive of bad response to treatment. Currently, we lack prospective long-term studies that will reveal the long-term benefit in overall survival and quality of life as result of the treatment. We also lack the data regarding the change in the cognitive and neuropsychology status of the patient as a result of the treatment. Another unsold issue is with recurrent disease. Some advocate repeat surgery before changing oncological regimen. Some will 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 already with radiotherapy and chemotherapy are ultimately rescued with other chemotherapy regimens with or without repeat resection.[56, 71] Several trials were published in regard to these questions. The results from the RTOG 9802 randomized trial[56, 58]  showed that low-risk LGG patients (those who had complete resection by postoperative imaging and are less than 40 years old) exhibited a 93% 5-year survival rate and a 5-year PFS (progression-free survival) of 48% without any adjuvant therapy. These results were very similar to those obtained by another important trial, EORTC 22845, which tested the patients for postoperative radiotherapy alone (either immediately after surgery or in progression) and found PFS in 5 years 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 of the LGG patients are young and survive longer, hence may show more than usual the 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.[44]

The use of chemotherapy in LGG has been studied widely and still is. In summary, for high-risk patients, the addition of PCV to radiation therapy markedly improves PFS, doubles OS, and seems to preserve cognitive function.[56] The use of temozolomide (alone or concomitant) instead or before PCV is still under research, but it seems at least comparable in terms of QOL and survival, and 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 subtotal resection is achieved or no resection is possible but biopsy, sometimes there is a need for multiple treatment regimens in order to halt progression of tumor growth.[61, 62, 63] The mortality in children tend to occur either from tumor-related case (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 a 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. 

Targated therapy 

In recent years, a lot of data has been published in regards to 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] In tumors that harbor the V600E mutation, treatment with BRAF inhibitors was shown to make 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]

 

Medication

Medication Summary

No specific drugs are recommended for treatment of low-grade glioma; however, certain conditions (in the setting of low-grade astrocytoma) typically require treatment like mentioned before: antiepileptic drugs, steroids, and so on.

Anticonvulsants

Class Summary

These agents are used to treat and prevent seizures.

Phenytoin (Dilantin)

In general, acts to block sodium channels and prevent repetitive firing of action potentials. As such, is very effective anticonvulsant. First-line drug in partial and generalized tonic-clonic seizures.

Carbamazepine (Tegretol)

Like phenytoin, acts by interacting with 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.

Levetiracetam (Keppra)

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.

Corticosteroids

Class Summary

These agents reduce edema around the tumor, frequently leading to symptomatic and objective improvement.

Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone, Baldex)

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.

 

Follow-up

Further Outpatient Care

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 (e.g. tectal gliomas specially 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 programable 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.

Further 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 anti epileptic 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.

Inpatient & Outpatient Medications

As described above, an anticonvulsant (if seizures are present) and dexamethasone (if edema is significant) are continued on an inpatient or outpatient basis. In addition, antiulcer medication is given with the corticosteroid for GI prophylaxis.

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.

Prognosis

As already discussed, 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.[17]

The molecular classification of low-grade diffuse gliomas[18] 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 follow-up only. In cases of tumor remnant or inability to perform surgical resection (ie, deep-seated lesions), the mortality tends to occur either from tumor-related factors or treatment morbidity. In one summary[61] , 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.