Infant-type hemispheric gliomas

INTRODUCTION — Infant-type hemispheric gliomas (IHGs) are rare high-grade gliomas affecting young children, primarily in the first year of life. With advances in molecular genetic characterization of central nervous system (CNS) tumors, IHGs are distinguished from histologically similar high-grade gliomas in older children and adults and recognized as a distinct entity in the 5^th edition of the World Health Organization (WHO) Classification of Tumors [1,2].

IHGs have a better prognosis than high-grade gliomas in older children despite the young age of patients at diagnosis and the need to omit, delay, or limit the dose of radiation to the developing brain.

This topic will review the pathology, clinical features, diagnosis, and management of IHGs. High-grade gliomas in older children, including histone 3 (H3) K27-altered diffuse midline gliomas, H3 G34-mutant diffuse hemispheric gliomas, and H3, isocitrate dehydrogenase (IDH)-wildtype high-grade gliomas, are discussed separately. (See "Diffuse intrinsic pontine glioma" and "High-grade gliomas in children and adolescents".)

EPIDEMIOLOGY — IHGs are extremely rare. Accurate incidence and prevalence estimates are not available because of how recently the tumor was recognized as a distinct entity.

There are no known genetic or environmental risk factors for IHG. They affect both sexes and do not demonstrate a predilection for certain ethnicities.

PATHOLOGY

Integrated histologic and molecular diagnosis — IHG is a newly defined diagnostic entity as of the 5^th edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (table 1) [1,2].

●Histopathology – IHGs are characteristically cellular and demarcated from adjacent brain parenchyma. Astrocytic cells often show ependymoma-like architecture. There are prominent areas of desmoplasia. Multiple high-grade features are present, including high cellularity, mitotic activity, high Ki-67 labeling, and necrosis [1,3].

●Methylation profile – IHGs form a distinct subgroup by methylation array profiling, regardless of the presence or absence of receptor tyrosine kinase (RTK) fusion events. Using unsupervised clustering analysis of deoxyribonucleic acid (DNA) methylation, IHGs forms a separate cluster from other more well-defined high-grade gliomas like glioblastoma, diffuse midline glioma, and isocitrate dehydrogenase (IDH)-mutant diffuse gliomas [4].

●Receptor tyrosine kinase fusion – All high-grade gliomas in infants should undergo RTK fusion testing by next-generation sequencing or fluorescence in situ hybridization [1]. Approximately 60 to 80 percent of IHGs harbor RTK fusions involving the neurotrophic tyrosine receptor kinase (NTRK) family of genes (NTRK1, NTRK2, NTRK3), ROS1, ALK, or MET. Tumors are subtyped according to the specific molecular alteration (eg, IHG, ROS1 altered).

Molecular pathogenesis — IHGs are enriched for structural genomic variants involving the fusion of RTK genes (NTRK1, NTRK2, NTRK3, ALK, ROS1, and MET) at the 3’ end with various genes as partners at the 5’ end. This causes constitutive activation of the kinase domain, activating the canonical phosphoinositide-3 kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways driving tumorigenesis [1,3-5]. Aside from these alterations, IHGs characteristically lack additional somatic mutations and have a flat genome with few large-scale copy number alterations [3].

CLINICAL FEATURES

Clinical presentation — IHGs present during infancy, with a median age at diagnosis of 0.36 years (range, 0 to 4.4 years) [3]. They are primarily located in the cerebral hemispheres and are nonmetastatic at diagnosis.

Clinical signs and symptoms depend on the age of presentation:

●Perinatal – A fraction of IHGs present at birth (congenital) or are suspected prenatally. Presenting signs and symptoms of congenital brain tumors may include [6-11] (see "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly"):

•Polyhydramnios

•Arrest of labor progression due to macrocephaly and dystocia

•Routine antepartum ultrasound showing an echogenic lesion in the brain, hydrocephalus, and/or an increase in biparietal diameter

•Prenatal magnetic resonance imaging (MRI) showing a diffuse lesion involving the cerebral hemispheres

•Stillbirth

•Hydrops fetalis

●Newborn/infant – Infants with IHG may present with:

•Macrocephaly

•Bulging, tense, and/or enlarged fontanelle

•Diastatic cranial sutures

•Lethargy/irritability

•Seizures

•Failure to thrive

•Inability to attain milestones

•Signs of sudden onset symptomatic intracranial hemorrhage (eg, hemiparesis, unresponsive infant)

●Young child – Young children with high-grade brain tumors may present with:

•Seizures

•Vomiting

•Headache

•Regression of milestones

•Refusal to walk

•Lethargy/irritability

•Unresponsive/loss of consciousness

•Signs of sudden onset symptomatic intracranial hemorrhage (eg, hemiparesis, unresponsive child)

Neuroimaging — MRI with contrast is the optimal modality to evaluate IHGs and other brain tumors. On MRI, IHGs are typically large, well-circumscribed tumors that sometimes involve the entire cerebral hemisphere. They are commonly hemorrhagic and cystic and have variable contrast enhancement. In approximately 50 to 60 percent of cases, the majority of the tumor volume (>75 percent) is occupied by hemorrhage [3].

Although MRI is highly suggestive of IHG based on imaging features and age of the patient, it is not diagnostic. Other tumors with overlapping imaging features in young children include supratentorial atypical teratoid/rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), other embryonal tumors, pediatric diffuse high-grade glioma, and ependymoma. (See "Uncommon brain tumors".)

DIAGNOSIS — Diagnosis of IHG requires tissue for histopathologic and molecular confirmation. Newborns, infants, and young children with presumptive (imaging) diagnoses should be transferred to a tertiary care center with pediatric neurosurgical and oncologic expertise for accurate molecular diagnosis and management. Upfront aggressive primary resection should be avoided and only attempted if clinically indicated for increased intracranial pressure. (See 'Risks of early resection' below.)

MANAGEMENT — IHG is a rare and novel entity, and there is no standard of care. Treatment decisions should be individualized with multidisciplinary input from neurosurgery and neuro-oncology teams with experience in rare infant brain tumors.

Care for IHG is evolving as effective targeted therapies have become available and are now being considered earlier in the treatment schema rather than at relapse or progression. Therefore, when feasible, these patients should be treated under well-monitored and regulated clinical trials.

Risks of early resection — IHGs are large, hemorrhagic tumors, and attempts at upfront complete resection are fraught with risk to the infant and the immature nervous system. Approximately 40 percent of craniotomies done for attempted gross total resection of IHG are complicated by massive hemorrhage, hypovolemic shock, and high transfusion requirements, and approximately 10 percent require a second neurosurgery within 48 hours in response to postoperative complications [3].

Based on these risks, surgical decisions should be made with abundant caution. Whenever clinically feasible, an initial diagnostic biopsy should be considered. Following tissue diagnosis, neoadjuvant cytotoxic chemotherapy can be used to cytoreduce and devascularize prior to attempting resection. The ultimate goal is to attain a complete or gross resection of the tumor safely and avoid acute and chronic morbidities.

Multiagent chemotherapy — Multiagent chemotherapy is the most common approach to the initial treatment of IHGs, including those with a receptor tyrosine kinase (RTK) fusion. Although case reports have shown the effectiveness of RTK inhibitors in the cytoreduction of IHG, such experimental therapies have limited short- and long-term toxicity data in infants. They should therefore be used cautiously and preferably as part of a clinical trial in this vulnerable population.

In historical trials of children with high-grade glioma treated with surgical resection followed by multiagent chemotherapy, those with tumors now classified as IHG have a five-year event-free survival of approximately 50 percent and overall survival of approximately 90 percent with this approach [3,12-15]. There are no published studies comparing the efficacy of various chemotherapy combinations, and the regimen offered depends on the treating team's preferences and experience. The most commonly used agents include cisplatin/carboplatin, alkylator therapy (cyclophosphamide), etoposide, and vincristine [3,12-15]. Rarely, methotrexate and topotecan have also been used [3].

When patients progress on primary therapy, other combinations of chemotherapy, targeted therapy, or more surgical resection are attempted; radiation is seldom required for cure. Despite high cure rates, however, survivors may often have poor quality of life. (See 'Prognosis' below.)

Avoidance of radiation — Radiation is avoided as both a frontline treatment and a treatment for relapsed disease due to the very young age of patients at diagnosis. In addition, studies have shown that radiation is not required to cure IHG [3,12-15].

Role of receptor tyrosine kinase inhibitors — Accumulating case reports and data from tissue-agnostic phase I/II trials indicate that molecularly defined treatment can lead to rapid cytoreduction and clinical recovery in patients with recurrent/progressive IHG with relevant fusions [11,16-25]. Activity has been demonstrated with tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK; eg, lorlatinib, alectinib), c-ROS oncogene 1 (ROS1; eg, entrectinib, lorlatinib), and tropomyosin receptor kinase (TRK) proteins A, B, and C (TRKA/B/C; eg, entrectinib, larotrectinib).

Although these case reports are promising, they are insufficient to identify the minimum effective dose, durability of response, adequate length of treatment, and long-term adverse effects of various TKIs in this age group. This knowledge gap has delayed the use of TKIs as first-line therapy in IHG; they are most often used as a compassionate/palliative care option in patients with recurrence/progression after multiple standard therapies including surgery and chemotherapy.

Participation in clinical trials is strongly encouraged. Although there are no trials in North America specific to IHG, several ongoing tissue-agnostic trials of TKIs permit enrollment of infants with IHG [26-28]. A searchable database is available through the United States National Library of Medicine. Outside of trials, relevant agents with US Food and Drug Administration (FDA) approval for treatment of infants with fusion-positive IHG include the following:

●Entrectinib – Entrectinib is a multikinase inhibitor of TRKA/B/C, ROS1, and ALK. It has tissue-agnostic approval in the US for adult and pediatric patients >1 month of age with NTRK gene fusion-positive solid tumors, including IHG. Efficacy, dosing, and toxicity are reviewed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Use in patients with central nervous system tumors'.)

●Larotrectinib – Larotrectinib is a selective inhibitor of TRKA/B/C. It has tissue-agnostic approval in the US for adult and pediatric patients with NTRK gene fusion-positive solid tumors, including IHG. Larotrectinib is available in a liquid formulation to support administration in young children. Efficacy, dosing, and toxicity are reviewed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Use in patients with central nervous system tumors'.)

PROGNOSIS — IHGs are malignant yet treatable tumors, despite challenges associated with their large and vascular nature and young age at diagnosis. Five-year overall survival estimates range from 50 to 90 percent and are more favorable than those in older children with high-grade glioma [3,12-15,29].

Unfortunately, survivors with IHG are faced with multiple challenges related to multimodality treatment of the nervous system at a young age, including poor neurocognitive outcomes, epilepsy, hemiplegia/paraplegia, disorders of speech and swallow, and endocrine deficiencies. Ongoing research and clinical trials are needed to identify better treatment approaches that preserve long-term survival while lessening the toxic effects of therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Infant-type hemispheric gliomas (IHGs) are rare malignant primary brain tumors affecting infants and young children with a median age of four months at diagnosis. There are no known genetic or environmental risk factors associated with IHG. (See 'Epidemiology' above.)

●Pathology – IHGs are cellular astrocytic neoplasms with multiple high-grade features, including high cellularity, mitotic activity, high Ki-67 labeling, and necrosis. Approximately 60 to 80 percent harbor gene fusions involving the neurotrophic tyrosine receptor kinase (NTRK) family of genes (NTRK1, NTRK2, NTRK3), ROS1, ALK, or MET. (See 'Pathology' above.)

●Clinical features – IHGs are primarily located in the cerebral hemispheres and are nonmetastatic at diagnosis. Signs and symptoms vary depending on the age at presentation. Infants most commonly present with macrocephaly, bulging fontanelle, lethargy, seizures, and failure to thrive. (See 'Clinical presentation' above.)

On MRI, IHGs are large, well-circumscribed, hemorrhagic tumors that sometimes involve the entire cerebral hemisphere. (See 'Neuroimaging' above.)

●Diagnosis – Diagnosis of IHG and other infantile brain tumors requires tissue for histopathologic and molecular confirmation. Infants should be transferred to a tertiary care center with pediatric neurosurgical and neuro-oncologic expertise in rare infantile brain tumors. It is critical to have an accurate diagnosis prior to treatment recommendations.

Pathologic diagnosis should be based on 2021 World Health Organization (WHO) criteria for central nervous system (CNS) tumors, which integrate histology, next-generation sequencing, and methylation profiling. (See 'Diagnosis' above.)

●Management – IHG is a rare and novel entity, and there is no standard of care. Treatment decisions are individualized with multidisciplinary input from neurosurgery, neuro-oncology, and radiation oncology. Care is evolving as effective targeted therapies have become available for tumors with NTRK, ROS1, and ALK gene fusions. (See 'Management' above.)

•After confirmation of diagnosis, for most patients, we suggest initial therapy with multiagent chemotherapy (Grade 2C). Surgery should be considered for patients with residual, resectable disease after chemotherapy with the goal of attaining gross total resection safely. (See 'Multiagent chemotherapy' above and 'Risks of early resection' above.)

•The role of targeted agents for patients with fusion-positive IHGs is evolving, and more safety and efficacy data are needed before they are used as frontline therapies in infants. Clinical trial participation is encouraged for this rare population.

In case of progression on chemotherapy, targeted inhibitors specific to the identified receptor tyrosine kinase alteration should be considered. Upfront targeted therapy instead of standard chemotherapy should be practiced with extreme caution, as this approach is not standardized or tested in clinical trials. (See 'Role of receptor tyrosine kinase inhibitors' above.)

●Prognosis – IHGs are malignant yet treatable tumors, despite challenges associated with their large and vascular nature and young age at diagnosis. Five-year overall survival estimates range from 50 to 90 percent. However, quality of life is often poor due to neurologic complications of the tumor and treatment. (See 'Prognosis' above.)