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Supratentorial Tumors in the Pediatric Population: Multidisciplinary Management
The most common pediatric supratentorial tumors include low-grade glioma, high-grade glioma (HGG), pineal region tumors, germ cell tumors, and intraventricular tumors. In this chapter, we examine the epidemiology, diagnosis, treatment, and relevant operative approaches for these lesions.
Epidemiology
Primary brain and other central nervous system (CNS) tumors are the most common solid tumors in pediatric patients and are the leading cause of cancer-related mortality in patients 0 to 14 years of age. CNS tumors account for 20% of all pediatric malignancies. In children 0 to 14 years of age the incidence of CNS tumors (nonmalignant and malignant) is 5.54 per 100,000—this incidence is higher in males (5.69 per 100,000) than in females (5.24 per 100,000). The incidence is highest in infants (<1 year old), followed by children ages 1 to 4 years old, and then by children in the 5 to 14 age group. Of note, the incidence of pediatric primary brain and CNS tumors is greatest in Caucasians and Asians/Pacific Islanders. Gliomas and embryonal tumors are more common in white children, whereas germ cell tumors of the cranial and spinal nerves are more common in Asians/Pacific Islanders.
The prevalence of primary brain and other CNS tumors for patients 0 to 14 years of age is estimated at 22.31 per 100,000; which leads to an estimate of 13,657 children living with the diagnosis in the United States. It is estimated that 3560 new cases of CNS tumors will be diagnosed in children 0 to 14 years of age in the United States in 2018. Overall survival (OS) for all CNS tumors (nonmalignant and malignant) in children 0 to 19 years old is 73.9%; however, this varies by tumor type and location. For supratentorial tumors, survival was 69.8% from 2002 to 2006.
The Central Brain Tumor Registry of the United States provides a comprehensive analysis of CNS tumors in the pediatric population ( Fig. 69.1 ). The distribution of CNS tumors is different across different age groups ( Fig. 69.2 ). For pediatric patients the distribution is also affected by age; the data is thus sensitive to which age group is being studied or presented ( Fig. 69.3 ). For patients 0 to 14 years of age, gliomas are the most common histology, accounting for around half of all patients with brain and CNS tumors. The most common glioma in this population is pilocytic astrocytoma (PA) (about one-third of all pediatric gliomas). Gliomas are followed by embryonal tumors, including medulloblastoma, atypical teratoid/rhabdoid tumor, and primitive neuroectodermal tumor, among others.
Infants have the highest incidence of embryonal tumors, germ cell tumors, choroid plexus tumors. In the subgroup of children less than 1 year old, the most common tumors are gliomas (37.2%), followed by embryonal tumors (24.9%), of which the most common one in this group is atypical teratoid/rhabdoid tumors (42.9% of embryonal tumors in this age group). For children 1 to 4 years old, gliomas account for 58.1% of tumors, followed by embryonal tumors with an incidence of 20.2%. PNET is at the highest incidence in the 0 to 4 years old population (PNET are now under a new classification of embryonal tumors). , In children 5 to 9 years old, the most common tumor histology is glioma (56.5%), followed by embryonal tumors (14.8%), of which, in this group, 80.4% are medulloblastomas. Medulloblastoma incidence peaks in the population at less than 9 years old, and incidence decreases with age. The subgroup of children 5 to 9 years old was found to have the highest incidence of HGGs in the population of children 0 to 14 years old. The distribution changes for children 10 to 14 years old: in this subgroup the most common histology is gliomas (48.6%), followed by pituitary tumors (8.9%) and embryonal tumors (8.3%). PA incidence peaks in the 0 to 9 years old age group, especially in the 1 to 4 age group, and declines with age. On the other hand, pituitary tumors increase in incidence during the teenage years. In terms of location in the brain, the cerebellum is the most common site of primary brain and CNS tumors in children 0 to 14 years old, accounting for 15.2% of tumors. This is followed by 13.4% of tumors located in the brainstem. For adolescents 15 to 19 years old, 32.1% of tumors are located in the pituitary of craniopharyngeal duct, which make it the most common site for this subgroup ( Fig. 69.4 ).
The Central Brain Tumor Registry classifies a location subgroup called “other brain” to encompass brain tumors that involve multiple locations or tumors whose location is not specified in the chart. This subgroup is the most common one for patients less than 1 year of age. In those patients 1 to 9 years old, the cerebellum is the most common site. For patients 10 to 14 years old, the most common site is hemispheric. , Supratentorial tumors constitute 31% of pediatric CNS tumors ( Table 69.1 ), , and predominate in patients under 3 years old and patients older than 10.
TABLE 69.1
Breakdown of the Anatomic Location of Pediatric Supratentorial Tumors
Matula C. Tumors of the pineal region. In Rengachary SS, Ellenbogen RG, eds. Principles of Neurosurgery . 2nd ed. Philadelphia: Elsevier; 2005.
| Supratentorial Brain Lesions | Patients (%) |
|---|---|
| Temporal lobe | 7 |
| Frontal lobe | 6 |
| Multilobar | 6 |
| Ventricle | 6 |
| Parietal lobe | 4 |
| Occipital lobe | 2 |
| Total patients | 31 |
Clinical Presentation
The clinical presentation is often determined by the tumor type and location, because symptoms are produced by local invasion, compression of adjacent structures, and increased intracranial pressure (ICP). The delay to diagnosis of a brain tumor in a child tends to be longer when compared to other childhood cancers; it has been reported from 1 to 27 months in the literature. More than 50% of patients have had symptoms for 6 months or longer at the time of diagnosis. The symptoms can be either focal/localizing or generalized. Focal/localizing symptoms result from direct pressure, irritation, or destruction of nearby neural structures by the tumor, causing impairment of function ( Table 69.2 ). Generalized symptoms are due to increased ICP, often a result of blockage of normal cerebrospinal fluid (CSF) flow. The most common generalizing symptoms for childhood CNS tumors include headache, nausea and vomiting, and lethargy. A meta-analysis was published in 2007 by Walker and colleagues studying the presentation of pediatric CNS tumors. Overall, the most common presenting symptoms were headache (33%), nausea and vomiting (32%), abnormal gait and coordination (27%), papilledema (13%), seizures (13%), and symptoms of increased ICP (10%). Though headache is the most common manifestation of CNS tumors in children, its character is nonspecific and can vary from focal to diffuse. The most frequent symptoms at the time of diagnosis of a supratentorial tumor were found to be nonspecific signs and symptoms of elevated ICP (47%), seizures (38%), and papilledema (21%). This study excludes central tumors from this supratentorial category; these are analyzed separately.
TABLE 69.2
Breakdown of the Most Common Presenting Symptoms for Pediatric Supratentorial Tumors
Matula C. Tumors of the pineal region. In Rengachary SS, Ellenbogen RG, editors. Principles of Neurosurgery . 2nd ed. Philadelphia: Elsevier; 2005.
| Presenting Symptom | Frequency (%) | Presenting Symptom | Frequency (%) |
|---|---|---|---|
| Headache | 33 | Declining academic performance | 7 |
| Nausea and vomiting | 32 | Macrocephaly | 7 |
| Abnormal gait or coordination | 27 | Cranial nerve palsies | 7 |
| Papilledema | 13 | Lethargy | 6 |
| Seizures | 13 | Abnormal eye movement | 6 |
| Intracranial pressure symptoms | 10 | Hemiplegia | 6 |
| Squinting | 7 | Weight loss | 5 |
Imaging
The options for imaging children include ultrasound if the fontanelle is open; x-ray, which can be of limited use in select cases; computed tomography (CT) with or without contrast; magnetic resonance imaging (MRI) with and without contrast; and if vascular abnormalities are suspected, magnetic resonance angiography (MRA), computed tomography angiography, or conventional angiography. The use of CT scans should be limited in the pediatric population, given the increasing evidence for radiation-induced malignancies that occur many years after image acquisition. Often an MRI with and without contrast will suffice. If neuroimaging does confirm the presence of a mass, tissue diagnosis is often necessary to determine the appropriate treatment regimen.
Low-grade Glioma
Epidemiology
Gliomas are the most common primary brain and CNS tumor found in patients 0 to 14 years of age, accounting for 52.9% of tumors. Low-grade gliomas arise from the glial cell line. This cell line gives rise to astrocytes, oligodendrocytes, and ependymal cells. Pediatric low-grade gliomas are a heterogeneous group of lesions that include tumors derived from these cell types, that is, PAs, oligodendrogliomas, and mixed neuroglial tumors. According to the Central Brain Tumor Registry of the United States, the most common glioma in the pediatric population is PA (33.2%), followed by what is defined as “other low-grade gliomas” by the authors and include oligodendrogliomas, diffuse astrocytoma, unique astrocytoma variants, oligoastrocytic tumors, and some tumors in the glioma malignant NOS category. The overall prognosis is favorable, with an indolent course and a remote risk of malignant transformation. While rare, there have even been case reports of spontaneous regression of low-grade astrocytomas.
Diagnosis
Currently, molecular evaluation of a low-grade glioma is essential for diagnosis and treatment of these tumors. Pediatric low-grade gliomas exhibit different molecular patterns and behaviors than adult low-grade gliomas. In the pediatric population, the molecular studies must include testing for BRAF mutations. Mutations causing abnormalities in the intracellular signaling via the Ras-mitogen-activated-protein-kinase (MAPK) pathway are found frequently in pediatric low-grade gliomas. Other important mutations to test for are isocitrate dehydrogenase (IDH) mutations and co-deletion of chromosome arms 1p and 19q. These are more common in the adolescent years through adulthood than in younger children. Assessment of presence or absence of these mutations is crucial for prognosis and treatment, as the tumors respond differently to various treatment modalities and new molecular targeted therapies are arising that can assist in treatment and improve patient survival. Despite the effectiveness of radiotherapy, its side effects and long-term increase in risk of tumors in the future make its use unappealing in young children. The goal is to avoid it when possible, especially in the very young. Some chemotherapy regimens have been found to be effective for tumor control for pediatric low-grade gliomas, but the 5-year event-free survival has been less than 60% for most tumors. There is a vast amount of ongoing research focusing on new ways to treat these tumors, including molecular targeted therapies, which can be expected to continue to change and improve patient outcomes in the future.
Tumors
Low-grade astrocytomas account for 30% to 50% of all pediatric CNS tumors, The two most common pediatric low-grade gliomas are PAs (World Health Organization [WHO] grade I) and diffuse astrocytoma (WHO grade II). PAs are typically found in children 5 to 19 years old, and the frequency decreases with age. The majority of PAs are considered WHO grade I, and can arise in different areas of the brain, with the cerebellum being the most frequent location in children (67%), followed by the supratentorial compartment (9.5%). , The most common supratentorial location of PAs is the optic pathway, contributing to approximately 60% of optic pathway gliomas (OPG). On imaging, a PA typically has a cystic component with an enhancing mural nodule. The solid component is isointense or hypointense on T1 and hyperintense on T2. The cystic wall can demonstrate enhancement in about half of cases. These tumors can also have a heterogenous appearance or be entirely solid. Histology demonstrates biphasic morphology. It has areas of compact tissue with abundant bipolar astrocytes with many processes and areas of more microcystic or myxoid tissue with scattered glia. Rosenthal fibers and eosinophilic granular bodies are present and assist in diagnosis. Molecular analysis is essential. Almost all PAs have a single mutation in the MAPK pathway (most frequently KIAA1549-BRAF or less commonly BRAF V600E). Rare anaplastic PAs and rare cases of malignant transformation have been described; however, in the majority of cases, survival is very favorable with a 10-year survival of over 90%. ,
The mainstay of treatment is complete surgical resection. Performing a complete resection is not always possible, especially in eloquent regions of the brain. If resection of the tumor is incomplete, surgery can be followed by radiation therapy and/or chemotherapy. Prognosis is not as favorable for patients with incomplete resection or for the rare cases of leptomeningeal spread.
Other less common pathologies of low-grade gliomas include pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma (PXA), ganglioglioma, subependymal giant cell astrocytoma (SEGA), and oligodendroglioma. A variant of PA is pilomyxoid astrocytoma (WHO grade II in the 2007 WHO Classification, but with recommendation for no definitive grade assignment in the 2016 WHO Classification of Gliomas). These tend to occur in infancy with a median age at diagnosis of 10 months; they typically arise in the hypothalamus or in region of the optic chiasm. On imaging they appear as heterogeneous masses with solid and cystic components. The solid component is isointense on T1 and may enhance. On T2, the solid components are hyperintense. Pathology demonstrates a myxoid background with bipolar astrocytes forming perivascular pseudorosettes. Rosenthal fibers and eosinophilic granular bodies are absent. , Given their common hypothalamic/chiasmatic location, these tumors are frequently not amenable to complete resection. This may contribute to their more aggressive behavior when compared to PAs. Pilomyxoid astrocytomas are also more likely to recur and to have CSF spread.
Gangliogliomas (WHO grade I) have also been shown to have frequent MAPK mutations similar to pilocytic astrocytomas, including BRAF V600E, and KIAA1549-BRAF fusion has also been identified. These tumors are more predominant in the pediatric population than in adults. They can arise anywhere in the CNS; however, the most common location is the temporal lobe. This explains why the most common presenting symptom for these tumors is seizures. Gangliogliomas are mixed tumors with ganglion cells and neoplastic glial elements. About half of the tumors have a cystic component. The solid component is isointense or hypointense on T1 and may enhance. On T2 the solid component is hyperintense. Edema around the tumor is rare and calcifications are common. Mainstay of treatment for supratentorial gangliogliomas is complete resection, which is curative. Radiotherapy can be given if resection is partial or if the tumor recurs. However, a repeat resection can be done in the case of recurrent tumor, as it is the only curative option. There is an anaplastic counterpart that is of higher grade.
PXAs are rare tumors that, like gangliogliomas, can present with seizures. They can arise anywhere in the brain, but they are almost always located in the supratentorial compartment (98%), especially in the temporal lobe, hence the presentation pattern. They are often peripherally located, involving the cortex, and can have a dural tail. These are classified as WHO grade II tumors. There is an anaplastic counterpart of higher grade and worse prognosis. PXAs are most commonly found in patients 10 to 30 years old. The sample sizes of studies focusing on these tumors are limited and studies include pediatric and adult populations showing that 15% to 20% of tumors can undergo anaplastic transformation. , Imaging demonstrates a peripheral enhancing nodule with an eccentric cyst (50% to 60%). As stated above, a dural tail can be seen. The solid component is isointense or hypointense on T1, it enhances, and is isointense or hyperintense on T2. The cyst shows low signal on T1 and high signal on T2. There may be surrounding edema. On histology specimens, pleomorphic appearance of the nuclei and the cells is present. The nuclei are of different sizes and have inclusions. The morphology of the cells varies—polygonal cells, giant astrocytes filled with lipid, and spindle cells are all seen. Eosinophilic granular bodies are seen. BRAF V600E mutations are common in PXAs (69%). Complete resection leads to a favorable outcome. If partial resection if achieved, radiotherapy or chemotherapy can be considered.
SEGA are WHO grade I lesions that are very strongly associated with tuberous sclerosis syndrome. It is seen in 5% to 20% of these patients. In all, SEGA accounts for 1.4% of pediatric tumors. The tumor arises from the ventricular wall near the foramen of Monroe. A small percentage of these tumors are diagnosed in the first months of life. However, the peak incidence is around 13 years old. Common presenting symptoms include symptoms from increased ICP due to obstructive hydrocephalus and worsening epilepsy. Imaging demonstrates an enhancing intraventricular lobulated mass. On T1 it is isointense or hypointense and on T2 it is heterogenous and isointense to hyperintense. Calcifications are common. Pathology specimens demonstrate clusters of large cells with abundant cytoplasm (gemistocytic-like cells, fibrillated spindle cells, and giant pyramidal cells) arranged commonly in perivascular pseudorosettes; lymphocytic infiltration is also seen. In patients with tuberous sclerosis, subependymal nodules are also seen and are of identical histology to SEGAs. SEGAs, however, demonstrate growth, albeit slow, but detectable on serial imaging. Treatment consists of complete resection, indicated for acute hydrocephalus, significant growth on serial imaging, or worsening seizures. Pharmacologic treatments are also used, such as everolimus and rapamycin to slow down growth and to reduce tumor size. These are contraindicated in cases of acute deterioration from elevated ICP due to hydrocephalus. Surgery is indicated in an emergent fashion in such presentation. Studies are ongoing regarding efficacy and outcomes of treating these tumors with Gamma Knife.
Oligodendrogliomas (WHO grade II) are rare and account for less than 5% of brain tumors in children. These tumors are rare in children, and the peak incidence is in patients who are 40 to 50 years old. The majority are supratentorial (85%), most commonly found in the frontal lobe. The most common symptom at presentation is seizures. These are infiltrative but circumscribed masses, typically in the cortical and subcortical region. Imaging shows a cortical/subcortical heterogeneous lesion that is isointense or hypointense on T1 and hyperintense on T2. About half of the tumors enhance and edema is minimal. Calcifications are very common (70% to 90%) and cystic areas can be seen. Histology demonstrates small round uniform cells with a perinuclear halo, giving oligodendroglioma cells their typical “fried egg” appearance, which is artifact from formalin fixation. The capillary structure is described as having a “chicken-wire” appearance. Mainstay of treatment is surgical resection. Molecular analysis is essential per the most recent WHO Classification of gliomas. All adult oligodendrogliomas are IDH mutants, but reports in children show a lower frequency, around 18%. Deletion of chromosome arms 1p and 19q is a marker of oligodendrogliomas in adults and this mutation confers sensitivity to chemotherapy. , In children, like IDH mutations, 1p/19q co-deletion is also less frequent than in adults. It has been reported in around 25% of cases and almost all of these patients were older than 16 years of age. Identification of these mutations assists in diagnosis, prognosis, treatment plan, and follow-up. Numerous research studies are ongoing to expand on the molecular characteristics of these tumors, and the molecular differences between tumors in children and adults, with the goal of finding new treatments.
Optic Pathway Gliomas
Epidemiology
OPG account for 3% to 5% of pediatric brain tumors; however, of brain tumors in patients 0 to 2 years old, 20% are OPG. , While they can present at any age, 75% become symptomatic in the first decade of life and 90% become symptomatic before age 20. The OPG can be located in the optic nerve, optic chiasm, optic tract, or optic radiations. In children, these are most frequently benign. The most frequent pathology is PA, but more aggressive types have been diagnosed and molecular markers assist with diagnosis and in predicting aggressive behavior of the tumors. , Some studies have identified a female predominance; this is not consistent in the literature. The signs and symptoms of OPG typically consist of decreased visual acuity, narrowing of visual field, proptosis, optic disc swelling, pendular movement nystagmus, a relative afferent pupillary defect, and strabismus. , Patients with large chiasmatic or hypothalamic lesions can present with signs and symptoms of elevated ICP. Patients can have vascular compromise of the optic apparatus from chronic compression of the central retinal vein, leading to occlusion, venous stasis retinopathy, optociliary shunt vessels, or neovascular glaucoma. In rare cases, acute loss of vision can occur in the setting of tumor hemorrhage. Patients typically do not present with orbital or ocular pain.
A firm link has been established between neurofibromatosis type 1 (NF1) and OPG. The incidence of NF1 among patients with OPG has ranged from 10% to 70% based on different series, while the incidence of optic nerve glioma in patients with NF1 varies from 8% to 31%. , OPGs represent 65% to 75% of all CNS tumors in children with NF1, and these primarily present before the age of 7. These tumors are most commonly unilateral, although many of the patients with NF1 develop bilateral optic nerve lesions (34.8%). Bilateral OPG are considered pathognomonic with NF1. Usually in patients with NF1, the OPG are more frequently in the optic nerve and do not extend intracranially into the chiasm or posterior optic pathway, which is different from sporadic OPG. , A number of OPG are diagnosed incidentally. About 30% to 50% of children with NF1 are symptomatic at diagnosis. At least 50% of children with NF1 and an OPG are asymptomatic. ,
The natural history of OPG is usually benign, with most growing slowly in a self-limited manner or, in extremely rare cases, spontaneously regressing. As a result, many patients retain excellent visual function or retain previous function without treatment. Diagnosis at a younger age is associated with poorer outcome in several studies. Sporadic OPG have been shown to have worse prognosis than those found in patients with NF1 and to present with symptoms, rather than being incidentally found prior to symptom development. , Seventy-four percent of these patients with sporadic OPG demonstrated progression despite treatment. Rarely, WHO grade III and IV lesions arise from the optic nerve and result in rapid visual loss, neurologic deficit, and eventual death. These high-grade lesions almost always occur in adults.
Diagnosis
The diagnosis of an OPG can largely be made by MRI of the brain and orbits with and without contrast. CT can also assist in diagnosis as enlargement of the optic nerve and remodeling of bony structures, such as the optic canal, can be seen. The radiographic appearance varies depending on whether the person has NF1. In patients without NF1, the optic nerve is almost always enlarged in a fusiform manner with a clear-cut margin produced by the intact dural sheath. In patients with NF1, the nerve is irregular, with kinking and buckling secondary to the mass. On MRI, the tumor is typically hypo- to isointense on T1-weighted imaging and hyperintense on T2-weighted imaging. Contrast enhancement is variable: some tumors may not enhance, while others can show patchy enhancement, or even avid enhancement ( Fig. 69.5 ). Additionally, MRI may demonstrate abnormalities that extend beyond the optic nerve into the chiasm. Patients may have an enlarged optic canal ipsilateral to the lesion, but this does not always indicate intracranial extension of the tumor. Arachnoid hyperplasia may be sufficient by itself to cause canal enlargement. Conversely, a normal caliber optic canal does not rule out the possibility of tumor extension beyond the orbit.
Pathology
Optic nerve gliomas often cause diffuse expansion of the nerve that may extend the entire length of the nerve or affect only a portion. The expanded portion can be solid or gelatinous, with hemorrhagic and necrotic regions. In children with NF1, the tumor not only expands the nerve but often breaks through pia mater and enters the subdural space. However, as long as the glioma lies within the confines of the orbit or optic canal, the tumors are typically limited to within the optic dural sheath. If the glioma extends intracranially, it can remain intraneural or become an expansile mass that can compress adjacent structures, including the chiasm or contralateral optic nerve.
The most common type of OPG is PA, which has three predominant histologic patterns: (1) coarsely reticulated, (2) finely reticulated, and (3) coarsely fibrillated or spindle cell. The most common pattern is coarsely reticulated, with a biphasic pattern histologically of coarse bipolar astrocytes that are either tightly compacted around blood vessels or loosely associated around microcystic spaces. These tumors frequently have Rosenthal fibers and eosinophilic granular bodies. Finely reticulated APs can be confused with WHO grade II diffuse low-grade astrocytomas and demonstrate an expansion of the indigenous neuroglia of the optic nerve. Within the finely reticulated tumors, a delicate reticulated syncytium of neuroglia fibers is embedded among multiple, small, round, or ovoid nuclei. The coarsely fibrillated variant consists of coarse neuroglial fibrils and spindle cells arranged in bundles and is more often seen in adults.
Patients with NF1 have a mutation in the NF1 gene, which produces neurofibromin. This ultimately leads to a deregulation of cell proliferation via activation of RAS and alterations in the MTOR pathway. , , Sporadic OPG have been found to be associated with a BRAF mutation. Research on the molecular characteristics of these tumors has increased in recent years with the aim of developing targeted therapies.
Management
Treatment of OPG continues to evolve. Management is highly variable, depending on the patient’s age, location of tumor along the pathway, degree of infiltration of the optic chiasm, visual function in both eyes, and whether the patient is comorbid with NF1. Patients with NF1 tend to have more indolent courses and develop symptoms at a later onset or remain symptomatic when compared to sporadic OPG.
Despite the increased frequency of OPG in children with NF1, there is no recommendation for routine surveillance imaging in asymptomatic children. In the past, the recommendation was to obtain imaging in children with NF1 that were younger than 6 years old or children with cognitive problems, as they may not be able to relay symptoms once these arise. However, decades of studies have not been able to prove any positive effect in prognosis, management, or even outcome (including frequency of visual dysfunction) when tumors were diagnosed earlier via serial imaging in asymptomatic children. , Some studies have recommended serial MRIs for children less than 15 months of age in order to identify tumors of higher risk in this population that is not able to relay symptoms. , The current recommendation is to perform yearly neurologic and ophthalmologic exams for patients with NF1 under 6 years old. After this age, some recommend to perform ophthalmologic exams every 2 years, as the incidence of developing an OPG decreases with age. , However, some experts advocate continued surveillance up to 25 years of age.
It has also been suggested that sporadic OPG patients, as opposed to OPG in patients with NF1, may benefit of serial imaging in combination with serial ophthalmologic exams once diagnosed since they are more likely to present already symptomatic, have a higher chance of progression, and have worse visual outcomes.
The time to treat OPG remains controversial. Most patients are managed conservatively. Research has not been successful at identifying predictors of progression. While no universally accepted criteria have been developed regarding when to treat OPG, most would agree that intervention is indicated if there is (1) progressive deterioration of visual function, (2) MRI findings of definite tumor enlargement or extension, (3) progressive neurologic deficit attributable to the tumor, or (4) cosmetically unacceptable proptosis or corneal exposure. Visual acuity is the most reliable monitoring tool when identifying symptomatic OPG. The definition of what constitutes significant deterioration in visual acuity has been debated and most experts define it as a decrease in two lines of visual acuity test. For newly diagnosed patients the recommendation is to obtain an ophthalmology evaluation, most importantly visual acuity, every 3 months and then expand that interval based on stability of the tumor and exam findings. ,
Some patients demonstrate radiologic regression spontaneously, while others demonstrate regression radiographically following treatment. However, this regression, whether due to treatment or spontaneously, does not always correlate with improved visual symptoms.
The three major treatment modalities are surgery, chemotherapy, and radiation therapy. Chemotherapy is usually the first line of treatment. The first-line regimen recommended is a combination of carboplatin and vincristine for both NF1-associated and sporadic OPG. A significant side effect of carboplatin is bone marrow suppression, so patients must be monitored. Other regimes have been developed for patients allergic to carboplatin.
Research shows that patients treated with radiotherapy have a 10-year progression-free survival (PFS) of 66% to 90%. , , However, radiation is controversial in young children given side effects like hormonal deficits, strokes, worsening visual symptoms, cognitive impairment, and ultimately long-term sequelae including secondary malignancies. More focused ways of delivering radiation may help decrease its negative effects: fractionated radiotherapy or proton beam radiation show promise in this regard. Currently radiation is avoided in NF1 patients given the increased risk of neoplasms in these patients. However, serious consideration for radiotherapy must be considered in adolescents and children who have failed chemotherapy.
Surgery still plays a role in the management of OPG, especially in individuals without NF1 for whom MRI findings are not compelling and tissue diagnosis is required. , Often in those cases, stereotactic or open biopsies can be safely performed. However, in cases where a large tumor creates mass effect on adjacent structures or leads to hydrocephalus, recurrent tumors refractory to chemo- or radiotherapy, or cystic lesions with compression of the optic pathway, can benefit from more radical surgery. Aggressive resection of tumors in the chiasmatic/hypothalamic region can lead to endocrinopathies and strokes. These risks have to be carefully weighed against the benefits of surgery prior to making the decision to undergo a surgical intervention. It is very rare that a tumor extends into the chiasm if it is not there upon diagnosis. For this reason, it is not recommended to resect a tumor to prevent extension into the chiasm. Advocates of aggressive surgical resection argue that radical tumor excision allows long-term remission, given the slow-growing nature of these tumors. Additionally, it could delay the need to initiate radiation therapy, which has significant long-term sequelae in children. While some studies have demonstrated that aggressive resection can safely be performed, the outcomes after surgery remain variable. Sawamura and colleagues reported on the visual outcomes after 26 cases treated surgically with the intent to debulk as much tumor as possible. Of this group, 20 patients underwent radical resection with greater than 90% tumor removal, and the remaining 6 patients had partial resection. Of the 26 children, only 2 had visual improvement, 2 remained static, 10 remained blind, and 12 worsened. Recommendation is to start chemotherapy once diagnosis is made via imaging. Tumors in the chiasm and posterior optic pathway should not be subjected to any surgery.
Given the unclear role for each of the treatment modalities and that the OS rate for pilocytic optic gliomas is greater than 90%, each patient should be treated in a case-by-case multidisciplinary fashion that involves pediatricians, neurologists, neurosurgeons, medical oncologists, and radiation oncologists. Preserving overall quality of life and vision should be key endpoints during the decision-making process.
A goal of ongoing research is to clarify the molecular fingerprint of these tumors to identify potential treatments with less side effects and better outcomes. Some of the trials currently underway include BRAF inhibitors, inhibitors of MEK, inhibitors of the mTOR pathway, as well as antiangiogenic therapies.
Thalamic Glioma
Brain tumors are the largest group of solid tumors and the leading cause of tumor-related death in children. In the pediatric population, there is a higher propensity of developing midline structure tumors (e.g., thalamus, brain stem, and spinal cord). Pediatric thalamic tumors are usually gliomas and tend to arise as primary gliomas or secondary gliomas from adjacent structures, including the cerebral hemispheres, caudate nuclei, brainstem, or pineal gland. The deep, central location of the midline structures makes surgical treatment of these tumors challenging. With the robust research in recent years, a better understanding of tumor biology and genetics leads us to more individualized treatment. Our knowledge regarding pediatric thalamic gliomas is based mainly on relatively small series. Gupta et al. published in 2017 a review of literature on pediatric thalamic gliomas. They found 45 publications, 20 were case reports, with a total of 445 cases of thalamic gliomas in patients less than 18 years of age (mean, approximately 9 years; range, 4.8 to 11.5 years).
Epidemiology
Neoplasms originating in the thalamus are rare overall (1% to 1.5% of all brain tumors); however, they comprise approximately 5% of pediatric intracranial tumors and approach 15% of all malignant pediatric intracranial tumors in some series. , In some series the incidence ranges from less than 1% to 5%, with possible explanation for this discrepancy being the difficulty in differentiating secondary involvement of the thalami from actual primary tumor rising from the thalami. There is no particular histology as they can be PAs, diffuse infiltrative astrocytomas and glioblastomas (GBMs). Higher-grade tumors tend to be more unilateral with less involvement of the optic pathways. The rare bilateral tumors harboring both thalami tend to be diffuse astrocytomas and have poor outcome mainly due to their intrinsic aggressive biology and the difficulty in attaining adequate surgical debulking of the tumor, resulting in mass effect on the thalamus, higher chances for obstructive hydrocephalus and lower effectiveness of adjuvant therapy in the presence of high tumor load. ,
New Era of Molecular Subtyping and Genetic Mutations
In 2016, with the publication of the WHO update on CNS tumors, a new organization of the midline structures tumors evolved now incorporating the new understanding of tumor genetics and molecular biology. , In the pediatric population, thalamic tumors are usually diffuse gliomas. Pediatric midline structure gliomas are now a narrowly defined group characterized by K27M mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, a diffuse growth pattern, and a midline location. , These tumors can be found in adults as well, although rarely. In the last update for WHO guidelines this group of tumors is termed diffuse midline glioma , H3 K27M–mutant, and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). Alternate histone mutations at position 34 (G34R) were also identified in hemispheric HGG, but not in midline structures or in pediatric low-grade glioma. , , , , We know today that the H3 K27M mutant can be found not just in HGGs but also in some low-grade gliomas, brainstem tumors as well as spinal cord tumors. For example, it was found in approximately 10% of thalamic low-grade glioma tumors. The distinction of low-grade gliomas from other midline neoplasms is determined by the presence of K27M mutant. A clear difference in survival is seen between tumors harboring the K27M mutation, in which all patients succumbed to their disease, as compared to the robust survival seen in non-K27M thalamic low-grade gliomas.
As in other pediatric low-grade gliomas, the presence of BRAF/MAPK mutations is common and can change the course of treatment. These alterations result in constitutive activation of BRAF, leading to potent MEK upregulation and overall activation of the MAPK pathway. Both the presence of BRAF V600E or the BRAF fusion (most commonly observed between BRAF and KIAA1549) can be found, with the V600E much more commonly found. In recent years, the presence of this mutation has become an important finding, enabling the potential use of targeted therapy.
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