Pediatrics

Low-grade Astrocytomas

Are you sure your patient has a low-grade astrocytoma?

Low grade astrocytomas (LGA) represent the most common group of pediatric brain tumors, with several histologic types arising at multiple sites within the central nervous system (CNS). The World Health Organization (WHO) categorizes LGA into grade I or grade II tumors, the majority of which are pilocytic and fibrillary or diffuse, respectively. Consultation with a neuropathologist with expertise in childhood brain tumors is highly advised.

What other disease/condition shares some of these symptoms?

Pilocytic Astrocytomas

Pilocytic astrocytomas (PA) have deceiving histologic and radiographic features that resemble more aggressive tumors (e.g., mitotic figures, endothelial proliferation, necrosis, and contrast-enhancement on magnetic resonance imaging [MRI] scans), although lack of perilesional edema often distinguishes them from higher grade tumors.

Fibrillary Astrocytomas

Fibrillary astrocytomas (FA) have a uniform histologic pattern of elongated nuclei and diffuse infiltration of surrounding gray and white matter. In contrast to PA, they typically do not show contrast enhancement on MRI.

What caused this disease to develop at this time?

Tumors may be present for years before they become symptomatic. A unifying feature of PA is an overactive mitogen-activated protein kinase (MAPK) signalling pathway occurring through several different types of mutations. They are frequently associated with neurofibromatosis type I (NF1), in which case they have a more indolent course. The remainder of PA have an overactive MAPK pathway because of mutations affecting the BRAF gene or from rare alterations in other signalling components.

In contrast, FA are less well characterized. Unlike adult gliomas, they typically lack p53 mutations but may be more likely to have mutations in IDH1/2, similar to oligodendrogliomas.

What you should be alert for in the history

Patients with LGA have neurologic symptoms referable to their location, often for months or even years before presentation.

Cerebral hemispheric lesions are likely to present with seizures.

Rare intraventricular lesions are usually silent until their growth results in symptoms of obstructive hydrocephalus, for example, headache, visual complaints, and mental status changes.

Most optic pathway and diencephalic astrocytomas cause visual complaints, but up to one third present with the "diencephalic syndrome," consisting of a "happy" personality and severe emaciation despite normal food intake, linear growth, and developmental milestones.

Focal brainstem lesions often cause cranial neuropathies, with or without obstructive hydrocephalus, often because of cerebral aqueductal compression.

Spinal astrocytomas often present with dysesthesias or focal pain, with variable motor deficits.

Any new finding of a CNS tumor in a child warrants a thorough clinical history encompassing symptoms originating from anywhere in the neuraxis (e.g., problems with mental status, cranial nerves, motor or sensory function, balance, or coordination).

Association With Inherited Disorders

Neurofibromatosis Type I

Physicians should be aware of associations between LGA and inherited disorders. Optic pathway and diencephalic astrocytomas are frequently associated with neurofibromatosis type I (NF1). Between 15% and 20% of patients with NF1 acquire optic pathway tumors, and approximately one third become symptomatic. Discovery of a tumor at this site should prompt the clinician to inquire about other evidence of NF1 in the patient or their family members (e.g., patches of discolored skin, freckling or other skin lesions, history of scoliosis, learning disabilities, or attention deficit hyperactivity disorder.

Tuberous Sclerosis

Subependymal giant cell astrocytomas (SEGA, WHO grade I) arise almost exclusively in the setting of tuberous sclerosis (TS). Suspicious lesions within the ventricles should prompt the clinician to inquire about other evidence of TS in the patient or their family members (e.g., seizures, developmental delay, behavioral problems, skin abnormalities, and disorders of the heart, lungs, or kidneys).

Characteristic findings on physical examination

For any neurologic examination, but especially in the case of a suspected brain tumor, visual acuity, visual field testing, and the fundoscopic examination are of paramount importance. Papilledema (i.e., bulging of the optic disc and blurring of the optic margins) is associated with intracranial hypertension and places the patient at risk for vision loss. Optic atrophy can be seen in association with optic pathway gliomas and confound the detection of intracranial hypertension. Other fundoscopic findings may include choroidal abnormalties and astrocytic hamartomas of the retina that can be associated with both NF1 and TS.

Especially in the setting of a lesion suspicious for optic pathway or diencephalic LGA, the clinician should be vigilant for additional physical findings associated with NF1, e.g., hypertension, short stature, macrocephaly, scoliosis, and the well-known features of café au lait spots.

In the setting of a known intraventricular lesion suspicious for SEGA, physicians should diligently examine the patient for physical findings associated with TS, for example, patches of discoloration (ash leaf spots), facial rashes (i.e., "adenoma sebaceum," periungal fibromas, and shagreen patches), as well as auscultatory findings on cardiac examination, such as arrhythmia and murmur that could be a sign of cardiac rhabdomyoma.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no helpful serum or urine laboratory markers. Cerebrospinal fluid analysis by lumbar puncture is not likely to provide helpful information unless the radiographic findings are uncharacteristic and there is disseminated disease.

Would imaging studies be helpful? If so, which ones?

The first step in the evaluation of LGA is MRI of the brain and spinal cord. Lesions are generally isolated to a single site, but multicentric lesions and dissemination do occur, most frequently in association with hypothalamic-chiasmatic tumors. It is important to image the entire neuraxis with contrast before surgical intervention because postsurgical blood products are difficult to discern from additional lesions.

Grade I LGA, (e.g., PA) are often cystic lesions that may resemble higher grade tumors because of gadolinium contrast enhancement.

Grade II LGA (e.g., FA) may range in appearance from a minor MRI T2 signal abnormality to diffuse thickening of gray matter structures and obliteration of normal anatomy.

Confirming the diagnosis

The diagnosis of LGA is confirmed only by histologic examination of biopsied tissue. In PA there is a classic, biphasic pattern of compact neoplastic cells and loose microcystic regions. Tumor cells have long, hair-like "pilocytic" processes and are associated with eosinophilic granular bodies. Rosenthal fibers are also characteristic, but similar findings occur with ganglioglioma or long-standing reactive gliosis in nonneoplastic conditions.

There may be foci of "fried egg" cells resembling oligodendrogliomas, and this confounding feature must be considered when the latter, more rare diagnosis, is proposed in children. There may also be inconsequential features that resemble aggressive tumors, for example, leptomeningeal extension and glomeruloid vascular proliferation, which accounts for contrast enhancement despite being low-grade tumors.

Diffuse astrocytomas (FA, WHO Grade II) are characterized by elongated nuclei in neoplastic cells diffusely infiltrating the surrounding gray and white matter. They lack the above mentioned biphasic pattern and Rosenthal fibers.

Molecular markers are currently not required for diagnosis but are the subject of current research because there may be significant biologic differences among LGA arising at different sites. For PA, staining with the proliferative marker Ki67 is usually positive in less than 5% of cells, above which the suspicion of grade II pilomyxoid astrocytoma should be raised.

The majority of non-NF1 PA contain an in-frame KIAA1549-BRAF gene fusion. In contrast, pleomorphic xanthoastrocytomas (PXA) often contain the BRAF V600E point mutation, and FA can have mutations in IDH1/2.

Who is at risk for development of the disease?

Many LGA are associated with neurofibromatosis type I (NF1). This autosomal dominant and sporadic disorder affects approximately 1/3,500 individuals worldwide and carries a predisposition to development of multiple tumor types. Up to one fifth of patients with NF1 acquire optic pathway and/or diencephalic LGA, causing significant visual and endocrinologic morbidity. Fortunately, NF1-associated LGA has a more indolent course than sporadic LGA at the same locations. The more common cerebellar PA do not have an association with NF1.

Intraventricular SEGA are much less common than PA and arise almost exclusively in the setting of TS. This autosomal dominant disorder affects 1/6,000 individuals with tumors of the brain, heart, lungs, skin, and kidneys. In up to one fifth of these patients, SEGA may arise from subependymal nodules, although this is controversial.

Overall, there are about 1,400 new cases of pediatric LGA per year in the United States. Among children older than four years of age, PA is the most common brain tumor, and before this age it is the second most common after medulloblastoma. For unknown reasons, white children are more commonly affected than are black children and, among all races, there is a slight male predominance.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Surgery

Surgery is the mainstay of therapy for LGA, as the extent of resection is the most important predictor of outcomes regardless of histologic subtype. After gross total resection (GTR), five-year progression-free survival (PFS) is around 90% and overall survival (OS) is close to 100%. In contrast, PFS after subtotal resection (STR) is at best around 60% and OS around 90%. Superficial tumors of the cerebral or cerebellar hemispheres are most amenable to GTR and have more favorable outcomes than do deeper seated or midline tumors (e.g., optic pathway, diencephalon, and brainstem tumors). For tumor recurrence after GTR, often the preferred treatment is repeat surgery.

Radiation

For patients who undergo GTR, radiation therapy (RT) is not indicated. The use of RT for subtotally resected or unresectable LGA has declined in recent years because of iatrogenic cognitive deficits, vasculopathy, endocrinologic disturbance, and risk of anaplastic transformation. Use of RT after STR was previously the preferred adjuvant therapy, but it has not shown significant survival benefit over that in patients not receiving RT. However, in some patients, RT becomes the only option for stalling or reversing neurologic deterioration.

Chemotherapy

The goal of chemotherapy for LGA is to delay or avoid RT at the time of tumor recurrence or progression after STR. Chemotherapy is often used before 10 years of age to defer RT until later when the developing CNS is somewhat more tolerant of injury from irradiation.

Two frequently used initial regimens include a combination of weekly carboplatin and vincristine, or a combination of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine, which has similar results. However, unlike RT, neither has shown survival benefit. Other chemotherapeutic regimens used at the time of relapse include temozolomide, actinomycin D/vincristine, bevacizumab, vinblastine, and oral etoposide.

Optimal Therapeutic Approach for this Disease

The optimal therapeutic approach depends on tumor resectability, which is the most important determinant of outcome. Superficial LGA of the cerebral or cerebellar hemispheres are most amenable to surgical resection and are associated with more favorable outcomes.

In contrast, LGA of the optic pathway, diencephalon, and brainstem are usually addressed surgically with stereotactic biopsy or partial debulking. Among these tumors, the optimal approach is less clear. Chemotherapy is used at the time of tumor progression or recurrence to delay the use of RT as long as possible. The accepted minimum age for RT ranges from eight to 10 years of age because of the risk for long-term complications in younger patients.

The frequency of MRI surveillance after therapy depends on the extent of surgical resection and clinical symptoms. Patients may undergo MRI every 3-6 months initially and change to yearly scans after evidence of stable disease or absence of residual tumor.

Patient Management

The severity of symptoms varies depending on tumor location and dictates the needs of each patient. Seizure management should be coordinated with a pediatric neurologist or neurooncologist. Almost all patients will require physical and/or occupational therapy.

Ophthalmic, endocrinologic, and neuropsychological evaluations are helpful as baseline studies, and referrals to educational specialists are often appropriate to establish individualized educational plans. Audiometry is required before and during many chemotherapy protocols.

Genetic testing may be helpful to patients and their families when NF1 or TS is suspected. Otherwise, genetic testing is not indicated for PA other than optic pathway and diencephalic lesions and is not helpful in other LGA with the exception of SEGA, which arises almost exclusively in the setting of TS.

What are the possible outcomes of this disease?

Complications of LGA may result from infiltration and destruction of critical CNS structures. There are no systemic manifestations of LGA other than lesions associated with the inherited disorders NF1 and TS and the adverse events from surgery or adjuvant therapy for this condition.

Cerebral hemispheric LGA such as PA, FA, and PXA are often associated with progressive motor, sensory, or cognitive deficits, in addition to seizures, which can result in bodily injury or be life-threatening in some circumstances.

Intraventricular SEGA and focal brainstem LGA may cause obstructive hydrocephalus, in which patients are at risk for obtundation and airway loss. Poor cerebral perfusion during uncontrolled elevations in intracranial pressure can have irreversible cognitive sequelae.

Optic pathway and diencephalic LGA cause visual deterioration and diencephalic syndrome, i.e., severe emaciation despite normal food intake, linear growth, and developmental milestones. Often a multidisciplinary approach is required for management of nutritional and endocrinologic concerns.

What causes this disease and how frequent is it?

In the subtypes of LGA in which molecular profiling has been performed, several aberrations have been identified in the MAPK pathway, a signaling cascade responsible for cell proliferation.

How do these pathogens/genes/exposures cause the disease?

In NF1-associated PA, the NF1 tumor suppressor gene is inactivated, leading to disinhibition of both MAPK and the mammalian target of rapamycin (mTOR), another signaling complex controlling cell proliferation and also implicated in SEGA development. In non-NF1 PA and PXA, constitutively active mutants of BRAF drive cellular proliferation through transcriptional activation.

Other clinical manifestations that might help with diagnosis and management

Unusual Clinical Scenarios to Consider in Patient Management

Patients may first come to medical attention for LGA because of new-onset seizures. This is likely to be the case for tumors of cerebral hemispheric location, either PA, FA, or PXA. Tumor-provoked seizures are often controlled initially with antiepileptic medications, but surgical resection is usually the treatment of choice to improve seizure control, psychosocial and intellectual development, and daily function.

Depending on tumor location, electrophysiologic and semiologic data, surgical options range from lesionectomy to resection of neighboring structures (e.g., portions of the mesial temporal lobe). Patients often wean slowly from antiepileptic medications after resection.

In patients with visual loss from an optic pathway LGA, surgical resection may be indicated for proptosis or exposure keratitis. Occasionally, tumor debulking with or without cerebrospinal fluid diversion is required to alleviate hydrocephalus or diencephalic symptoms.

In contrast to LGA at other sites, extent of resection does not have any survival benefit, as these tumors already have a very low mortality rate by natural history. The same can be said for chemotherapy and RT, and thus other measurements of features such as visual function and tumor size may be applied to measure response rates. Unfortunately, there appears to be no correlation between radiographic progression and visual deterioration, making clinical decision making difficult in younger children, in whom optic pathway LGA are most common.

Patients with intraventricular tumors, exophytic diencephalic lesions, or focal brainstem lesions may present in extremis with obstructive hydrocephalus. These patients require cerebrospinal fluid diversion in the form of an extraventricular drain, ventricular shunt, or endoscopic third ventriculostomy. They may initially require several days of hospitalization, including intensive care, for recovery from these procedures.

The clinician must be cognizant of the possibility for failure of a shunt or third ventriculostomy at any time, which will result in neurologic deterioration. Patients with magnetically programmable ventricular shunts require verification that their shunt valve remains at the appropriate setting after MRI.

Patients with cerebellar LGA often have the most favorable outcomes because their lesions are the most amenable to complete resection. However, because of their location, they may produce cerebellar deficits, such as appendicular ataxia and gait instability. These patients should always be formally assessed by physical and occupational therapists. Cerebellar dysfunction in children may also result in cognitive disturbances even without RT or chemotherapy. Neuropsychological testing may therefore be useful in all patients receiving treatment for LGA, regardless of its location.

What complications might you expect from the disease or treatment of the disease?

See What are the possible outcomes of this disease?

How can low-grade astrocytomas be prevented?

Prevention/Avoidance

There are no preventive measures for LGA, but early detection may be possible in the hands of an astute pediatrician. In young children, routine pediatric physical examinations should include assessments of developmental milestones and measurements of head circumference. Delayed development, early hand preference or coordination below that expected for age, or macrocephaly may prompt more detailed evaluation, potentially including brain imaging and referral to a child neurologist. Subtle signs such as head tilt or mild dysconjugate gaze may have insidious onset and be more obvious in family photographs.

Expert consensus statements recommend against baseline MRI scans following diagnosis of NF1 because asymptomatic lesions do not warrant treatment. However, imaging should be performed on patients with confounding factors that make detection of symptoms difficult or unreliable.

Since up to one fifth of patients with NF1 eventually experience optic pathway LGA, annual ophthalmic screening is recommended. Ophthalmologic rather than radiographic screening may be preferred because two thirds of radiographically detected tumors do not progress or become clinically significant. Which visual function tests are the most useful for detecting new symptomatic disease is still a matter of debate.

Screening of patients with TS includes brain MRI every 1-3 years. If growth of a subependymal nodule (possibly the precursor to SEGA) is detected, the frequency of imaging is increased. A careful history in these patients should include positional headaches, worsening of seizures,visual complaints, or nausea and vomiting.

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