Pediatrics

Low-grade Astrocytomas

OVERVIEW: What every practitioner needs to knowAre 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 LGAs into grade I or grade II tumors, the majority of which are pilocytic and fibrillary or diffuse, respectively. Consultation with a neuropathologist who is expert in childhood brain tumors is highly advised.

What other disease/condition shares some of these symptoms?

Pilocytic Astrocytomas

Pilocytic astrocytomas (PAs) 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. They are frequently associated with neurofibromatosis type I (NF), in which case they have a more indolent course. Recent molecular profiling indicates the majority of non-NF1 PAs contain an in-frame KIAA1549-BRAF gene fusion that drives unchecked growth.

Fibrillary Astrocytomas

Fibrillary astrocytomas (FAs) have a uniform histologic pattern of elongated nuclei and diffuse infiltration of surrounding gray and white matter. In contrast to PAs, they typically do not show contrast enhancement on MRI. Unlike adult gliomas, they typically lack p53 mutations but may be more likely to have mutations in IDH1/2, similar to oligodendrogliomas.

What caused this disease to develop at this time?

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 are reported to acquire optic pathway tumors, and approximately one third become symptomatic. Whether these numbers are biased by institutional series is unknown. 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 increased intracranial pressure and places the patient at risk for vision loss. Optic atrophy can be seen in association with optic pathway gliomas even in the absence of papilledema. 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 astrocytoma, the clinician should be vigilant for additional physical findings associated with NF1, for example, 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 rarely 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 often 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.

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.

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 be aware that similar findings occur with ganglioglioma or long-standing reactive gliosis in nonneoplastic conditions.

Physicians should be also aware that PAs often have 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) of 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 LGAs arising at different sites. For PAs, 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.

Recent molecular profiling studies indicate that the majority of non-NF1 PAs contain an in-frame KIAA1549-BRAF gene fusion. In contrast, pleomorphic xanthoastrocytomas (PXAs) often contain the BRAFV600E point mutation, and FA can have mutations in IDH1/2.

Who is at risk for development of the disease?

Many LGAs are associated with neurofibromatosis type I (NF1). This autosomal dominant and sporadic disorder affects approximately 1/3500 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 PAs do not have an association with NF1.

The SEGAs are much less common than PAs and arise almost exclusively in the setting of TS. This autosomal dominant disorder affects 1/6000 individuals with tumors of the brain, heart, lungs, skin, and kidneys. In up to one fifth of these patients, SEGAs may arise from subependymal nodules, although this is controversial.

Overall, there are about 1400 new cases of pediatric LGA per year in the United States. Among children older than 4 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), the 5-year progression-free survival (PFS) is around 90% and overall survival (OS) is close to 100%. In comparison, after subtotal resection (STR), the PFS is at best around 60% and the 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 repeated 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 (CV), or a combination of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV), which has similar results.

Although both achieve responses for a few patients and "stabilize" the disease for the majority of children, most clinicians prefer CV. However, neither regimen, like RT, 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 LGAs of the cerebral or cerebellar hemispheres are most amenable to surgical resection and are associated with more favorable outcomes.

In contrast, LGAs 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. Practice patterns have shifted toward using chemotherapy at the time of tumor progression or recurrence to delay the use of RT as long as possible. The accepted minimum age for RT has varied between institutions and countries, ranging from 8-10 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 PAs other than optic pathway and diencephalic lesions and is not helpful in other LGAs 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 CNSstructures. There are no systemic manifestations of LGA other thanlesions associated with the inherited disorders NF1 and TS and theadverse events from surgery or adjuvant therapy for this condition.

Cerebralhemispheric LGAs such as PA, FA, and PXA, are often associated withprogressive motor, sensory, or cognitive deficits in addition toseizures, which can result in bodily injury or be life-threatening insome circumstances.

IntraventricularSEGA and focal brainstem LGA are often complicated by obstructivehydrocephalus. In this condition, patients are at risk for obtundationand airway loss. Poor cerebral perfusion during uncontrolled elevationsin intracranial pressure can have irreversible cognitive sequelae.

Optic pathway and diencephalic LGA cause visual deterioration and diencephalic syndrome, that is, severeemaciation despite normal food intake, linear growth, and developmentalmilestones. Often a multidisciplinary approach is required formanagement of nutritional and endocrinologic concerns.

What causes this disease and how frequent is it?

In the subtypes of LGAin which molecular profiling has been performed, several aberrationshave been identified in the mitogen-activated protein kinase (MAPK)pathway, a signaling cascade responsible for cell proliferation.

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

InNF1-associated PA, the NF1 tumor suppressor gene is inactivated,leading to disinhibition of both MAPK and the mammalian target ofrapamycin (mTOR), another signaling complex involved in controlling cellproliferation and also implicated in the mechanism of SEGA development.In non-NF1 PA and PXA, constitutively active mutants of BRAF drive cellular proliferation through activation of downstream proteins involved in gene transcription.

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 LGAs 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 LGAs 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 (ETV). 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 the shunt or third ventriculostomy at any time, which will result in neurologic deterioration. Patients undergoing MRI with programmable ventricular shunts require verification that their shunt valve remains at the appropriate setting after imaging. Neurologic deterioration in patients after ETV should prompt imaging with thin sagittal T2 sequences to confirm patency of the ventriculostomy.

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. Some recent studies suggest that cerebellar dysfunction in children may also result in cognitive disturbances even without RT or chemotherapy, but this is not well understood. 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 nopreventive measures for LGA, but early detection may be possible in thehands of an astute pediatrician. In young children, routine pediatricphysical examinations should include assessments of developmentalmilestones and measurements of head circumference. Delayed development,early hand preference or coordination below that expected for age, ormacrocephaly may prompt more detailed evaluation, potentially includingbrain imaging and referral to a child neurologist. Subtle signs such ashead tilt or mild dysconjugate gaze may have insidious onset and be moreobvious in family photographs.

Initial brain MRI is usually performed on diagnosis of NF1, but since up to one fifth of patients with NF1 eventually experience opticpathway LGA, annual ophthalmic screening is also recommended in thesepatients to identify potentially new symptomatic LGA for appropriatereferral and treatment. Ophthalmic rather than radiographic screeningmay be preferred because two thirds of radiographically detected tumorsdo not progress or become clinically significant. Which visual functiontests are the most useful for detecting new symptomatic disease is stilla matter of debate.

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

What is the evidence?

Wisoff, JH, Sanford, RA, Heier, LA. "Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group". Neurosurgery. vol. 68. 2011. pp. 1548-55.

(The authors, all authorities in the field of pediatric brain tumors, prospectively followed 518 patients for disease control and survival after surgery for low-grade gliomas.The rates of 5-year PFS and OS were 80% and 97%, respectively. In multivariate analysis, gross total resection was the main predictor of PFS.)

Fisher, PG, Tihan, T, Goldthwaite, PT. "Outcome analysis of childhood low-grade astrocytomas". Pediatr Blood Cancer. vol. 51. 2008. pp. 245-50.

(The authors retrospectively reviewed a consecutive cohort of 278 patients with surgically confirmed LGA to determine the long-term outcomes with respect to histologic subtypes and treatments.The rates of 5-year PFS and OS were 55% and 87%, respectively. Among patients with residual tumor after surgery, immediate postoperative radiation did not confer a survival advantage.)

Packer, RJ, Ater, J, Allen, J. "Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas". J Neurosurg. vol. 86. 1997. pp. 747-54.

(In this classic paper that has guided much of current clinical practice for LGA, 78 children with low-grade gliomas received a regimen of carboplatin and vincristine if they experienced tumor enlargement and/or clinical deterioration before surgery removing less than half of the mass.The regimen achieved a 5-year PFS of 48%, with complications of thrombocytopenia, peripheral neuropathy, allergic reactions, and one case of fatal sepsis. However, there was objective response to therapy in 56%. It is important to keep in mind that despite a lack of survival benefit, the preservation of vision and/or neurologic function may be worthy goals of adjuvant therapies.

Tatevossian, RG, Lawson, ARJ, Forshew, T. "MAPK pathway activation and the origins of pediatric low-grade astrocytomas". J Cell Physiol. vol. 222. 2009. pp. 509-14.

(This is a concise and accessible review of recently described molecular mechanisms underlying the development of pediatric LGA. Specifically, these tumors often have aberrations in the MAPK pathway, a signaling cascade important in cell proliferation.Tumors associated with NF1 have inactivation of a tumor suppressor gene product, leading to constitutive activation of the downstream components Ras, Raf, Mek, and Erk, which regulate gene transcription. Non-NF1–associated tumors often have Raf mutations that lead to dysregulation of the same pathway.)

Campen, CJ, Porter, BE. "Subependymal giant cell astrocytoma (SEGA) treatment update". Curr Treat Options Neurol. vol. 13. 2011. pp. 380-5.

(Here the authors provide a concise review on the current treatments of SEGA, with specific emphasis on mutational disruption of the mTOR signaling pathway and the use of mTOR inhibitors as an adjunct therapy.)

http://www.cbtrus.org/reports//2004-2005/2005report.pdf.

Farmer, JP, Montes, JL, Freeman, CR. "Brainstem gliomas: a 10-year institutional review". Pediatr Neurosurg. vol. 34. 2001. pp. 206-14.

Fried, I, Hawkins, C, Scheinemann, K. "Favorable outcome with conservative treatment for children with low grade brainstem tumors". Pediatr Blood Cancer. vol. 58. 2012. pp. 556-60.

Louis, DN, Ohgaki, H, Wistler, OD. "World Health Organization classification of tumours of the central nervous system". IARC. 2007.

Mansur, DB, Rubin, JB, Kidd, EA. "Radiation therapy for pilocytic astrocytomas of childhood". Int J Radiat Oncol. vol. 79. 2011. pp. 829-34.

Merchant, TE, Kun, LE, Wu, S. "Phase II trial of conformal radiation therapy for pediatric low-grade glioma". J Clin Oncol. vol. 27. 2009. pp. 3598-604.

Mishra, KK, Puri, DR, Missett, BT. "The role of up-front radiation therapy for incompletely resected pediatric WHO grade II low-grade gliomas". Neuro Oncol. vol. 8. 2006. pp. 166-74.

Mishra, KK, Squire, S, Lamborn, K. "Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update". J Neuro Oncol. vol. 100. 2010. pp. 121-7.

Pollack, IF, Claassen, D, Al-Shboul, Q. "Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases". J Neurosurg. vol. 82. pp. 536-47.

Uliel-Sibony, S, Kramer, U, Fried, I. "Pediatric temporal low-grade glial tumors: epilepsy outcome following resection in 48 children". Childs Nerv Syst. vol. 27. 2011. pp. 1413-8.

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