Rare brain embryonal tumors in infancy and early childhood

General Child Neurology

Updated 08.14.2024
Released 06.13.1995
Expires For CME 08.14.2027

Rare brain embryonal tumors in infancy and early childhood

Authors: Palma Solano Páez MD, Adriana Fonseca MD

See Contributor Disclosures

Editor: Roger J Packer MD

Rare brain embryonal tumors in infancy and early childhood

In This Article

Quick Link

Introduction

Overview

Embryonal brain tumors account for approximately 13% of primary brain tumors of childhood, following gliomas as the second most common CNS tumor type in children up to 14 years of age (67; 72).

Brain tumors may be congenital in children younger than 3 years of age and range from benign complex lesions to highly malignant neoplasms. They differ from those in older children with regard to histology, presentation symptoms, and treatment options, with historically lower survival outcomes. The most recent Central Brain Tumor Registry of the United States (CBTRUS) statistical report estimated brain tumor incidence in children 0 to 4 years of age to be 6.18/100,000 population, which exceeds the incidence in children aged 4 to 14 years (5.5/10000) (72). Approximately 10% to 15% of all childhood brain tumors will appear in the first 2 years of life, and about half occur in the first 6 months; overall, they are considered rare. Embryonal tumors represent 25% of brain tumors in infants younger than 1 year of age (73; 23).

The World Health Organization 2021 Classification (WHO CNS5), based on an integrated taxonomy with a strong emphasis on molecular profiling, established two types of embryonal tumors: medulloblastomas and other CNS embryonal tumors. Medulloblastoma is the most common embryonal brain tumor, whereas other embryonal tumor types are considered “rare” and typically affect infants and very young children. In contrast to medulloblastomas, which by definition originate from the cerebellum or dorsal brainstem, other CNS embryonal tumors may arise across the neuraxis.

Rare embryonal tumors were previously classified as either medulloblastomas or supratentorial primitive neuroectodermal tumors “sPNET,” and they represent approximately 34% of all embryonal brain tumors of children and adolescents (73; 72). The term sPNET is now obsolete and was removed from the WHO 2016 Classification of CNS tumors, thanks to an increased understanding of the heterogeneity and biology of these tumors and the emergence of a classification based on molecular characteristics.

Due to the unique features of the population affected by these entities, rare embryonal tumors deserve specific understanding, comprehensive diagnostic tools, and the development of much-needed novel tailored treatment approaches prioritizing less-toxic therapies to the immature nervous system.

In this article, the authors provide an overview of current concepts of clinicopathologic characteristics, specific molecular diagnosis, and general treatment strategies for these rare embryonal tumors of childhood. WHO CNS5 defines three main entities: embryonal tumor with multilayered rosettes (ETMR), CNS neuroblastoma FOXR2-activated, and CNS tumor with BCOR internal tandem duplication. Recent advances in the molecular diagnosis and treatment of pineoblastoma, a rare embryonal tumor of the pineal gland with particular penetrance in infants and young children, are also highlighted in this review. The common embryonal brain tumor medulloblastoma and the rare atypical rhabdoid teratoid tumor are well-defined entities in terms of their histopathological features, immunophenotype, and genetic profiles, as are other brain tumors occurring in this age range, including choroid plexus tumors and infant gliomas, and they are discussed in separate articles.

Key points

	• Although uncommon in children younger than 2 years of age, primary CNS tumors at this age comprise almost 15% of all childhood brain tumors.
	• Non-medulloblastoma embryonal brain tumors are considered rare entities; however, they account for 25% of central nervous system tumors affecting children under 1 year of age.
	• Rare embryonal tumors may be congenital and can arise along the neuraxis. They can present as large tumors occupying contiguous cerebral lobes or as primary pineal, brainstem, or spinal cord tumors.
	• Main new entities of embryonal brain tumors with defined genetic driver events include embryonal tumor internal tandem duplication.
	• Molecularly defined aggressive pineoblastoma subgroups affect mainly infants and very young children.
	• Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumors are poorly defined. Moreover, the development of much-needed innovative therapies is warranted for rare pediatric embryonal tumors.

Historical note and terminology

Over the past decade, genomic, transcriptomic, and proteomic profiling on large collections of embryonal brain tumors has revealed tumor heterogeneity, with proposed subgroups characterized by distinct molecular drivers (95; 91). The introduction of increasingly specific tumor groups is an effort to create more internally homogeneous categories, to allow more precise prognostication, and potentially to develop targeted therapies. New entities of embryonal brain tumors affect predominantly infants and very young children and were originally included in the WHO 2016 classification and further reviewed and updated in the latest WHO CNS5 (Table 1).

Table 1. Embryonal Brain Tumors of Infant and Young Children

Infant medulloblastoma
	Medulloblastoma, SHH activated Medulloblastoma non-WNT, non-SHH (Groups 3 and 4)
Rare embryonal brain tumors
	Atypical teratoid or rhabdoid tumor Cribriform neuroepithelial tumor (CRINET) Embryonal tumor with multilayered rosettes (ETMR) CNS neuroblastoma, FOXR2-activated CNS tumor with BCOR internal tandem duplication (BCOR-ITD) CNS embryonal tumor not elsewhere classified/not otherwise classified
Embryonal tumors of the pineal gland
	Pineoblastoma
		Pineoblastoma, MYC/FOXR2 activated Pineoblastoma, RB1-altered (pineal retinoblastoma) Pineoblastoma miRNA-1 and miRNA-2
(106)

Whereas ETMR was included in previous WHO classifications, CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR-ITD are new to WHO CNS5. In addition, CNS5 recognizes an ETMR with DICER1 alteration (in addition to the more common ETMR, C19MC altered). CNS tumors with BCOR-ITD are now included in WHO CNS5 as embryonal tumors, but these neoplasms are not definitively neuroectodermal.

Clinical manifestations

Presentation and course

General clinical manifestations of rare embryonal brain tumors in infants and young children. The signs and symptoms of brain tumors in children younger than 2 years of age, especially those younger than 1 year, differ significantly from manifestations seen in older patients (13). Many rare embryonal tumors are believed to be congenital, and they present during times of maximum brain growth and development (66; 62). They occur when the child's skull is able to expand, resulting in the development of macrocephaly and often masking the signs and symptoms of increased intracranial pressure. Time between onset of symptoms and diagnosis has been noted to be longer for children younger than 3 years of age with medulloblastomas compared to older children (81).

As with central nervous system neoplasms in older patients, presenting signs and symptoms are partially related to the location of the tumor within the nervous system, and they are mostly non-tumor-type specific.

Non-medulloblastoma embryonal tumors can arise along the CNS with a predominance for the supratentorial compartment; this applies especially to CNS neuroblastoma, FOXR2-activated, which has only been reported in supratentorial locations (46; 106). ETMRs can arise across the neuraxis. Supratentorial location ranges between 45% to 70%, depending on the series, and the frontal lobe is the most frequent site of origin (25; 42). CNS BCOR-ITD shows an equal preference for peripheral location both in the cerebral and cerebellar hemispheres (21; 10). These rare embryonal neoplasms peculiarly present as large tumors, frequently traversing lobes or occupying both supra- and infratentorial compartments. Ten percent of ETMR, and rarely CNS BCOR-ITD, can present in the brainstem, with radiological and clinical manifestations mimicking diffuse pontine gliomas. Few cases of primarily spinal rare embryonal tumors have also been reported, representing 3% of ETMRs (69; 87; 54).

Embryonal tumors of the pineal region usually cause symptoms of mass effect, including headaches, aqueductal stenosis, and hydrocephalus. Parinaud syndrome, secondary to mass effect on the tectum and characterized by upward gaze palsy, pupillary light-near dissociation, and convergence retraction nystagmus, is a typical finding of patients with pineal tumors.

Metastatic disease at diagnosis varies amongst tumor-type entities. In ETMR, it ranges from 18% to 25% with both macroscopic intracranial or spinal leptomeningeal spread and microscopic invasion of the CSF reported--and occasionally with extracranial invasive growth and extradural metastases (90; 21; 42). Not surprisingly, brainstem location and metastatic disease are both adverse prognostic factors, with only a few reported survivors (42). Seventeen percent of CNS NB FOXR2 are metastatic at diagnosis (102). In contrast, there are no reported cases of metastatic CNS BCOR-ITD at presentation, although it is the most common pattern at relapse of this rare tumor type (21). The French report published by Hortwitz and colleagues in 2016 described the main clinical symptoms at presentation in 38 patients diagnosed with ETMR at a median age of 31 months (34). Presenting symptoms included sided weakness (34%), increased intracranial pressure (53%), and cerebellar syndrome (21%). Seizures occurred in 21% of patients; 8% presented with torticollis, and visual impairment was found in 11% (34).

Children younger than 2 years of age with posterior fossa tumors usually present with vomiting. Incoordination or other evidence of cerebellar dysfunction can be difficult to determine in a young child, and younger children with posterior fossa tumors are as likely, or more likely, to present with delayed milestones and altered sensorium. Most patients will have some evidence of increased intracranial pressure due to both the bulk of the tumor and obstruction of cerebrospinal fluid flow. Both supratentorial and infratentorial tumors may result in macrocephaly. Sometimes this is due to obstructive hydrocephalus, and other times it is primarily due to the large bulk of the lesion (66); this applies especially to children with rare embryonal tumors that frequently present with very large tumors. A proportion of children (23%) under the age of 3 years have tumor-related seizures at presentation (98); furthermore, young age was found to be inversely related to the onset of seizures in children with a brain tumor in a multivariate analysis (84). Due to their embryonal nature, this subset of tumors has a high cellular turnover and a rapid-growing pattern, with some patients presenting with worsening symptoms due to tumor progression even during the course of therapy. A presentation unique to infants and young children is a delay or an arrest of developmental milestones. Infants and children may also present with unexplained irritability and failure to thrive, with little in the way of localized neurologic deficits.

Embryonal tumor with multilayered rosettes (ETMR)

In 2000, Eberhart and colleagues first described embryonal tumor with abundant neuropil and true rosettes as a new histological category of brain tumors (19). The term embryonal tumor with multilayered rosettes was proposed in 2010 as a unifying entity because the histological central element found in these tumors was the presence of multilayered rosettes. Subsequent molecular studies showed various rare histological entities diagnosed as primitive neuroectodermal tumors, including embryonal tumors with abundant neuropil and true rosettes, medulloepithelioma, and ependymoblastoma; these tumors shared recurrent amplification or gene fusions of the microRNA cluster on chromosome arm 19q13.42 (C19MC) and primitive transcriptome enriched for LIN28A--a pluripotency factor that is, however, not completely specific for ETMR (56; 48). These studies led to the designation of C19MC-altered ETMRs, which were initially included as a new entity in WHO CNS4 in 2016 (95). WHO CN5 defines ETMR as a grade 4 embryonal neoplasm conforming to one of three morphological patterns (embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, or medulloepithelioma), typically having a C19MC alteration or (rarely) a DICER1 mutation (100; 44). Significant contributions in ETMR epidemiology and clinical and treatment prognostic factors have emerged, with the largest series of molecularly confirmed ETMR with paired clinical data published by European and North American Groups.

Prognosis and complications

ETMR is characterized by particularly aggressive behavior, with typical survival of 1 year after diagnosis despite intensive therapy and no consensus on treatment approach. These tumors typically affect very young children, with a median age at presentation of 2.5 years (range 0.5 to 8). Unlike other pediatric brain tumors, a slight predominance in females has been found in some studies (25; 34; 42), whereas the gender ratio has been reported to be almost balanced in other series.

Clinical vignette

A previously healthy 18-month-old girl presented with a history of 2 weeks of progressive left-sided upper and lower limb tremors, unsteady gait, and frequent falls. On examination, the child was alert and playful. She was able to stand unsupported but had a broad-based ataxic gait, postural tremor of her left body, left pendular patellar reflex, and mild decreased tone of her lower left limb.

MRI revealed a T1 hypointense and T2/FLAIR hyperintense solid tumor with cystic areas located in the right thalamus, crossing midline and causing obstructive triventricular hydrocephalus. The tumor was non-contrast enhancing and had no surrounding edema. It showed diffusion restriction. No intracranial or spinal metastatic lesions were noted. Gross total resection of the tumor was achieved with no new neurologic deficits. CSF cytology performed 2 weeks after surgery was negative for malignant cells. Histology showed an embryonal tumor with cellular areas composed of pleomorphic cells with hyperchromatic nuclei and scant cytoplasm arranged in nodules, sheets, and multilayered perivascular rosettes on an abundant neuropil-like stroma. Immunohistochemistry revealed LIN28A positivity and patchy synaptophysin and GFAP positivity. BAF47 (INI1) in tumor cells was retained. Amplification of the C19MC locus was detected by interphase fluorescence in situ hybridization analysis. The final diagnosis was localized supratentorial ETMR C19MC-altered.

Radiology and pathology features of embryonal tumor with multilayered rosettes

(TOP ROW) MRI shows typical features of ETMR in an 18-month-old girl. There is a well-delimited, large supratentorial intra-axial mass within the right thalami, measuring 4 x 3.8 x 3.8 cm and crossing midline and causing mild s...

Three cycles of postoperative intensive chemotherapy, including cisplatin, cyclophosphamide, carboplatin, methotrexate, and vincristine, were delivered. However, MRI performed after chemotherapy revealed rapid tumor regrowth, infiltrating the right thalamus, which was considered not amenable to complete surgical resection. The patient’s parents declined further therapy and opted for palliative care. The patient died of disease progression 7 months after initial diagnosis.

Biological basis

Genetics. ETMRs have few recurrent genetic aberrations, mainly affecting the microRNA (miRNA) pathway and including amplification of C19MC (ETMR, C19MC-altered) and mutually exclusive biallelic DICER1 mutations of which the first hit is typically inherited through the germline (ETMR, DICER1-mutated). DNA copy-number aberrations, such as gain of chromosome 2, have been reported in approximately 70% of ETMR cases. Other chromosome arms altered include 1q, 3q, 7p, 7q,11q, and 17q gains and loss of 6q (25; 56).

C19MC alteration and DICER1 mutation drive genetic aberrations in ETMR

ETMR C19MC-altered. The characteristic chromosome 19 miRNA cluster amplification of the 19q13.42 locus, named C19MC, was first described in 2009. C19MC is usually focally amplified, but fusions can also occur, generally with TTYH1 (56; 47). C19MC is now considered the genetic hallmark of ETMRs, present in approximately 90% of all ETMRs regardless their histology. ETMR, C19MC-altered was first added as a tumor subtype to the WHO CNS Classification in 2016.

ETMR with DICER1 alteration. Uro-Coste and colleagues described in 2019 the first two cases of DICER1 mutations in two consecutive infantile cerebellar embryonal tumors not otherwise specified, with histological features consistent with ETMR, immunopositivity for LIN28, and chromosome 2 gain but without C19MC locus alteration. Both patients were found to carry DICER1 mutations in the germline (100). By sequencing 82 ETMRs, including 16 samples of ETMR-C19MC negative, Lambo and colleagues noted that all DICER1 mutations occurred in patients who lacked the C19MC amplification (49). They concluded that in patients with ETMRs where the driver C19MC was not amplified, the tumors were significantly more often located in infratentorial regions and frequently had germline mutations in DICER1 or other microRNA-related aberrations. Importantly, most DICER1-mutant ETMRs arise based on a DICER1 mutation within the germline, a cancer predisposition condition termed DICER1 predisposition syndrome. Therefore, genetic testing and counseling should be prompted in this subset of patients. Based on the above-mentioned studies, ETMR-DICER-1 mutated has been added as a new ETMR subtype in WHO CNS5.

Therefore, the term ETMR not elsewhere classified should be restricted to the remaining rare ETMR without a C19MC alteration or DICER-1 mutation. It has been suggested that ETMR-NEC may be driven by amplification of the miR-17–92 microRNA cluster on chromosome 13 (49; 50).

LIN28 is upregulated in ETMRs. All ETMRs, despite their highly heterogeneous histology, are characterized by high expression of the RNA-binding protein LIN28A. LIN28A encodes proteins implicated in several cellular processes, including metabolism, tumor transformation, and progression, and is widely expressed in embryonic stem cells (99). High expression of LIN28 has been associated with unfavorable prognosis in certain types of adult cancers and pediatric neuroblastoma by promoting angiogenesis, metastasis, and cell death resistance, amongst other mechanisms of action (03).

In ETMRs, overexpression of LIN28A has been shown to regulate tumor growth (92). LIN28 focal immunopositivity also can be observed in a small subset of atypical rhabdoid teratoid tumors, high-grade gliomas, and CNS germ cell tumors (09; 94; 83). Therefore, LIN28 immunopositivity is considered a useful marker; however, it lacks specificity to diagnose ETMR.

Pathology

Both DNA methylation profiling and transcriptome analysis have clearly demonstrated that embryonal tumors with abundant neuropil and true rosettes, ependymoblastomas, and medulloepitheliomas constitute various points along a morphological spectrum of diverse differentiation within a single tumor entity. Although the histological patterns in ETMRs are diverse, characteristic features are commonly observed. Rosettes are a characteristic histological feature of multilayered structures consisting of embryonal cells mitotically active in a pseudostratified neuroepithelium with a central lumen. All morphological patterns of ETMR show abundant mitotic figures and apoptotic bodies, indicating a high cell turnover rate, with Ki-67 proliferation index ranging from 20% to 80%. After therapy, some ETMRs show neuronal and glial differentiation, and this has been related to less aggressive tumor behavior. Strong and diffuse cytoplasmic immunoreactivity for LIN28A is found in ETMRs irrespective of their morphological pattern (45).

Epidemiology

ETMRs may likely represent a relevant proportion of the previous category “CNS-PNET”; however, there is a lack of data on the true incidence and prevalence of this rare entity due in part to the historical misdiagnoses for these tumors and the lack of molecular tools for its diagnostic confirmation until recent years. Based on the prospective German P-HIT Trial, Juhnke and colleagues estimated the incidence of ETMR to be 1.35 per 1 million children aged 1 to 4 years (41).

Prevention

No method of prevention is known for rare CNS embryonal tumors. However, germline testing for tumor predisposition syndromes, such as DICER-1 in DICER-mutant ETMR and pineoblastoma mRNA1 and 2, and mutations in the RB gene in children diagnosed with pineoblastoma RB-altered are mandatory and will be further discussed (16; 58).

Differential diagnosis

Confusing conditions. Intraocular medulloepithelioma and sacrococcygeal ependymoblastoma share some histopathological features with CNS ETMR but harbor striking molecular differences and, consequently, deserve a separate nosological designation (05; 33).

Associated or underlying disorders. No genetic susceptibility for patients with ETMR, C19MC-altered has been reported. However, the report presenting the molecular landscape in a large cohort of ETMRs at diagnosis and relapse performed by Lambo and colleagues found that the formation of structural variants in ETMR genome is an early event in tumorigenesis. Moreover, they found strong conservation of clustered breakpoints between primary tumors and their matched relapse samples occurring in close proximity to C19MC, generating the hypothesis of a possible genetic predisposition that leads to C19MC amplification in ETMRs (50).

In contrast, as discussed above, almost all patients with ETMR-DICER1 mutant carry a pathogenic DICER1 germline alteration, which should prompt genetic testing and counseling. DICER1 is inherited as an autosomal dominant condition with decreased penetrance. Therefore, the children of individuals with a DICER1 pathogenic variant have a 50% chance of inheriting the mutation. DICER syndrome predisposes to a broad spectrum of benign and malignant tumors, including the most common pediatric pleuropulmonary blastoma, in which pathogenic germline DICER1 variants underlie more than 70% of cases. Other CNS tumors have been described in DICER1 syndrome, including pineoblastoma subgroups PB-miRNA processing altered-1 and PB-miRNA processing altered-2 (16; 58) and ciliary body medulloepithelioma (89; 33).

Therefore, ETMR, DICER1-mutant can represent the first clinical manifestation of a cancer predisposition syndrome in a young child with no family history of cancer due to the known decreased penetrance of DICER1; moreover, it should be added to the long list of conditions associated with DICER1.

Diagnostic workup

Diagnostic workup of rare embryonal brain tumors should include brain and spine contrast MRI with diffusion-weighted sequences. Staging of microscopic metastatic disease should be performed by lumbar puncture on day +14 following initial surgery or biopsy. Further imaging, such as body PET scan or extracranial imaging, is only indicated in cases of suspected extra CNS involvement at diagnosis or during the course of the disease. Children with pineoblastoma, RB altered should have periodic ophthalmology surveillance. CT brain scan use should be restricted for emergencies only, and low radiation techniques should be encouraged in young children to avoid cumulative adverse effects of ionic radiation in the developing brain.

Imaging. On MRI, ETMRs are typically very large tumors with frequent calcifications, little-to-no surround edema, and absent or weak contrast enhancement, giving a misleading benign appearance. ETMRs may occasionally display intratumoral large vessels. They show restricted diffusion that reflects dense cellularity (103; 15; 36).

Management

ETMRs represent a therapeutic challenge to clinicians as no uniform standard treatment protocols are available. They are characterized by a highly aggressive clinical course, treatment resistance, frequent tumor recurrence, and rapid death.

The scarce clinical data in ETMR published until 2015 referred to heterogeneously treated patients and showed poor survival, with historic survival rates of less than 10%. Most recent studies explored treatment-related prognostic factors in molecularly confirmed ETMR and suggested that these patients might benefit from multimodal therapeutic approaches, reaching survival rates up to 27%. Moreover, in these reports, survival rates for children with ETMRs located outside the brainstem ranged between 33% to 47%. Prospective survival analyses weighing the independent impact of each specific treatment modality in ETMR have not been performed; therefore, the following comments on the potential benefit of the different treatment modalities delivered are based on exploratory analysis of mainly retrospective cohorts.

Role of extent of surgical resection in ETMRs. Surgical resection remains a vital component of most treatment algorithms as the initial step in managing most pediatric brain tumors. It has consistently been reported that total or near-total resection of the primary tumor correlates with improved outcomes, especially in patients with nondisseminated disease (51).

A neurosurgical approach of rare embryonal brain tumors in infants and young children can be challenging due to the relatively large volume of tumors in this population and the location in deep-sited cerebral structures and supratentorial eloquent areas, which usually hinders extensive tumor resections (66). However, the average of gross total resections achieved in ETMRs demonstrated a significant proportion of totally resected tumors. The French Society of Pediatric Hematology and Oncology reported 38 ETMR patients (10 confirmed with molecular diagnoses), and 17 of 38 (44%) benefitted from a gross total resection (34). Similarly, the multi-institutional Canadian Rare Brain Tumor Consortium (RBTC) reported on 108 molecularly confirmed ETMRs treated with curative intent and observed 45% (49 of 108) of the patients achieved a gross total resection (42). Both cohorts are retrospective, and the latest included 12 patients with ETMRs located in the brainstem, in which a gross total resection could only be achieved in one patient. The most recent German Prospective P-HIT Trial retrospectively identified 35 ETMRs by molecular analysis and observed a 40% (14 of 35) gross total resection rate. This series included four patients with unresectable brainstem primary tumors, and all succumbed to disease within 10 months after diagnosis (41). Brainstem location, as already mentioned, represents an independent adverse prognostic factor in these and other series, with only anecdotal long-term survivors of brainstem ETMRs reported (69; 87; 54; 42).

The mentioned reports confirmed gross total resection as a positive prognosticator in ETMRs, achieving a 4-year overall survival of 39% versus 23% in patients with subtotal resection. Furthermore, second-look surgery should be considered in selected cases because some long-term survivors benefitted from it, and the survival in patients with subtotally resected tumors remains very poor, with almost universal progression of disease in patients with subtotal resection even during the course of therapy. However, due to the retrospective nature of these analyses and the heterogeneous treatment modalities delivered, the impact of other adjuvant therapies, such as intensive chemotherapy or radiation in sub-totally resected tumors, has not yet been fully elucidated.

Response to chemotherapy in ETMRs. ETMRs, like other embryonal tumors, have demonstrated chemosensitivity, with reported maintained remissions and objective responses achieved following chemotherapy after surgery (102). However, the benefit of specific chemotherapy agents in ETMR has been difficult to assess because there have been few large series of patients homogeneously treated. The choice of chemotherapy for ETMR described in the literature has been based on a historic selection of drugs commonly used for embryonal-type brain tumors included in a variety of protocols (European PNET-High Risk, the German HIT/SKK, SJMB96, SJMB03, U.S. cooperative group protocols CCG99703 and ACNS0334, PBTC026, as well as Head Start protocols II and IV). Commonly used chemotherapy includes platinum and etoposide-based induction therapy with or without cyclophosphamide, vincristine, or high-dose methotrexate. The above-mentioned chemotherapy regimens lack a specific rationale for ETMR because no standard chemotherapy approach is specifically designed for this rare disease.

Hanson and colleagues reported the excellent outcome of five patients with totally resected, nonmetastatic, non-brainstem ETMRs treated with the Dana-Farber Cancer Institute-modified IRS-III protocol (DFCI-IRS-III) that was initially developed for atypical rhabdoid teratoid tumors, adding doxorubicin and actinomycin D to a platinum-based embryonal chemotherapy backbone, including intrathecal methotrexate with radiation delivered to four of five patients in their report (29). The rationale for the addition of these drugs commonly included in sarcoma protocols was the study by Schmidt and colleagues who found D-actinomycin and doxorubicin to be active in an in vitro and in vivo preclinical drug screen using a patient-derived ETMR cell line (88).

The large Canadian RBTC report, which included patients treated with diverse chemotherapy approaches, could not find superiority of any specific multiagent induction or conventional chemotherapy regimens. Methotrexate has been historically incorporated into some pediatric embryonal brain tumor protocols, intravenously or directly into the CNS compartment by intrathecal injection or intraventricular devices (85; 86). However, methotrexate is a neurotoxic agent that can add significant acute and long-term side effects to this vulnerable and heavily treated population (18; 71). Remarkably, preliminary results of the ACNS0334 protocol observed no difference in survival by methotrexate randomization in the subset of fourteen enrolled patients with ETMRs (65). Therefore, we suggest that methotrexate should not be delivered to patients with non-medulloblastoma embryonal tumors out of the context of a clinical trial.

Less intensive induction chemotherapy strategies also have been explored and suggested to be effective in ETMR. The Vienna group reported two of nine survivors with totally resected ETMRs who received temozolomide and intrathecal therapy in contrast with seven remaining patients who received high-dose chemotherapy and succumbed to disease. However, the two survivors were the only radiation recipients in the cohort; therefore, this survival benefit should not be merely attributed to a less intensive chemotherapy strategy (63). Similarly, in the French cohort, a long-term survivor with a totally resected ETMR was treated with temozolomide and irinotecan, followed by craniospinal radiotherapy (34).

Treatment strategies based on high-dose chemotherapy and autologous stem cell rescue to defer or avoid neurocognitive sequelae of radiotherapy have been widely used in young patients with malignant brain tumors (22; 96; 06; 12; 11). Studies have reported survival outcomes of patients with ETMRs who received high-dose chemotherapy to be superior to those who received conventional chemotherapy regimens. The German group found the HIT-P induction chemotherapy backbone with carboplatin and etoposide and subsequent administration of tandem high-dose chemotherapy containing etoposide/carboplatin and thiotepa/cyclophosphamide achieved superior outcome probabilities compared to other approaches with conventional chemotherapy only, with 5-year PFS and overall survival probabilities of 35% (95%CI:19% to 67%) and 47% (95%CI: 28% to 78%) compared to 0% and 8% (95%CI: 1% to 55%) (41). Similarly, the Canadian registry reported a significant survival benefit in patients treated with heterogeneous high-dose chemotherapy strategies, with a 4-year overall survival of 24% (95% CI:38% to 52%) versus 15% (95%CI:0% to 30%) in those treated with conventional chemotherapy only (42). The French report also identified the administration of high-dose chemotherapy as an independent positive prognosticator for survival in a subset of 38 patients with ETMR, 30 of them homogeneously treated within the European HR-PNET protocol (34).

Considerations of radiotherapy in ETMRs and other rare embryonal tumors. Due to the intent to avoid or delay CNS radiation at a young age, the timing, dose, and extent of radiation field prescribed in ETMR patients have been heterogeneously adapted according to patient characteristics, disease course, and response to other adjuvant therapies received, such as surgery or chemotherapy. Radiotherapy emerged as an independent prognosticator of survival in several studies and reports (34; 74; 64; 42) and is considered by some authors an effective and essential component in the treatment strategy of ETMRs. By contrast, other studies did not find radiation therapy to positively contribute to survival in ETMR (41).

Radiation-sparring strategies have been proposed for a selected proportion of infants with localized and totally resected ETMR who received high-dose chemotherapy and achieved EFS and overall survival of 31% and 41%, respectively, in the Canadian Registry. The authors of this study found that the addition of radiation represented an important survival benefit in patients with sub-totally resected ETMRs who also received high-dose chemotherapy, with observed EFS of 34% and overall survival of 63%. Overall survival outcome of 65% was reported for the subset of radiated patients with non-brainstem, nonmetastatic, and totally resected tumors who received high-dose chemotherapy (42).

Considering the uncertainties in establishing a uniform indication for radiotherapy in ETMRs, recommendations on more specific aspects, such as the extent of the radiation field and radiation timing, are still uncertain. Some authors have reported long-term survivors who benefited from craniospinal radiation (24; 61; 34; 39). However, based on the pattern of ETMR progression and relapses predominantly observed locally (34; 64; 42) and considering the deleterious effects caused by neuroaxis radiation, use of focal radiotherapy when appropriate seems reasonable in localized ETMRs. This is supported by reports of many survivors in different studies who received radiotherapy confined to the tumor bed only (29; 63; 42; 41).

ETMR “early progressors” have been historically identified, with a median EFS of 1 to 7 months typically observed and most of the tumor progressions and relapses occurring within 1 year from diagnosis (34; 42; 41). In their series of nine patients with ETMR in whom radiotherapy was deferred, Mayr and colleagues reported that seven patients had recurrence despite intensive chemotherapy and succumbed to their disease (64). The German series reported four survivors who received upfront radiation following surgery. These and similar observations have supported the recommendation by some authors of early focal radiation in ETMR following, for example, two cycles of chemotherapy.

In conclusion, the indication, extent, and timing of radiation in ETMR patients should be carefully considered in relation to patient-specific risk features and response to adjuvant therapies. The increasing accessibility to proton facilities represents an opportunity to reduce the neurocognitive damage and endocrine sequelae these young patients suffer.

Intrathecal and intraventricular chemotherapy in rare embryonal tumors. Intrathecal and intraventricular administration of chemotherapy has been extensively used in infant brain tumor protocols to prevent or diminish tumor cell leptomeningeal dissemination throughout the cerebral spinal fluid (93; 85; 52; 80; 04; 74). Delivery of cytotoxic agents into the CSF compartment usually aims to avoid or delay radiation, particularly craniospinal; furthermore, it may act prophylactically in leptomeningeal spreading in focally radiated patients. Reports on intrathecal chemotherapy in ETMRs are mostly based on personalized treatment strategies, and few series of homogeneously treated patients have been reported, with insufficient data to analyze its potential impact in survival. Anecdotal reports have demonstrated the sensitivity of ETMR to intrathecal drugs. Gessi and colleagues described the transient resolution of leptomeningeal metastases following intrathecal chemotherapy in a patient with disseminated ETMR (25).

The German HIT-P protocol included intraventricular methotrexate in the backbone induction and found superior survival outcomes for patients treated with homogeneous induction containing carboplatin and etoposide and high-dose chemotherapy (41). However, the actual impact of intraventricular methotrexate was hampered as it was equally delivered to patients receiving other induction schemas.

Hanson and colleagues reported on five patients with ETMR treated according to the modified ISRS III protocol (29). They described a heterogeneous combination of intrathecal chemotherapy, including methotrexate, cytarabine, and/or topotecan concomitantly with induction chemoradiation and, in one patient, during maintenance. They reported one relapse during induction in a patient treated with intrathecal chemotherapy and no radiation. Based on these observations, they have developed an international prospective ETMR consensus protocol that includes multiagent intravenous and intrathecal chemotherapy, with or without high-dose chemotherapy and radiation.

The report from Vienna on nine patients with ETMR treated with heterogeneous induction protocols and intrathecal chemotherapy, including etoposide, cytarabine, and/or topotecan, observed seven relapses, all focal (64). The authors concluded that intrathecal therapy could have prevented leptomeningeal dissemination in this small cohort. However, focal recurrences are the most common pattern of progression and relapses in ETMRs, with the use of intrathecal chemotherapy upfront not documented in most patients. Furthermore, most survivors of ETMR did not receive intrathecal chemotherapy. Nevertheless, including intrathecal chemotherapy into ETMR treatment strategies might be of interest due to the proven chemosensitivity of CNS embryonal tumors and the clinical characteristics of this population who are highly vulnerable to the detrimental effects of radiation.

The drugs of choice for this route of administration should ideally be selected based on preclinical ETMR models. Topoisomerase inhibitor topotecan demonstrated activity against ETMR in in vivo studies (88) and has been delivered intrathecally in ETMR in some of the above-mentioned studies. The neurologic toxicity profile of chemotherapy agents administered to the CSF must be carefully weighted to design a safe drug combination regimen or to modify pre-existing schemas, especially if radiation is planned. Serious acute and long-term adverse events related to intrathecal and intraventricular chemotherapy administration in pediatric brain tumor protocols have been reported (80; 74).

CNS neuroblastoma, FOXR2-activated

CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2) is an infrequently encountered, histologically-defined embryonal neoplasm. It represents the most favorable prognosis entity amongst the rare embryonal brain tumors of childhood. “CNS neuroblastoma” was first described by Bailey and Cushing in 1959 as the “infrequent occurrence of a cortical medulloblastoma.” In 2016, The important findings by Sturm and colleagues identified a distinct group of tumors delineated by DNA methylation profiling from a broad analysis of tumors previously diagnosed as CNS PNET, which was characterized by chromosomal rearrangements leading to activation of the transcription factor FOXR2 (95).

The 2021 edition of the WHO Classification of CNS Tumors introduced CNS NB-FOXR2 as a molecularly defined entity.

Epidemiology and clinical features

CNS NB-FOXR2 tumors arise in young children (median age 5 to 8 years, range 2 to 16 years). Age at presentation is usually older than for patients with ETMR, and the gender ratio appears to be preponderant in females in some series, whereas other reports show a balanced gender distribution (95; 46; 102; 59). Only supratentorial CNS NB-FOXR2 tumors have been reported, with most cases arising from the cerebral hemispheres and some anecdotal reports of intraventricular location (95; 32). CNS metastases have been reported in up to 17% of cases (102).

Pathology

CNS NB-FOXR2 is an embryonal neoplasm exhibiting varying degrees of neuroblastic or neuronal differentiation, including foci of ganglion cells (ganglioneuroblastoma) and frequent necrosis and vascular proliferation. A helpful clue to the diagnosis is the presence of widespread nuclear immunopositivity for Olig2. These tumors are also synaptophysin-positive and usually GFAP- and vimentin-negative. TTF-1 (NKX2.1) overexpression is present in most of these tumors and may be a useful immunomarker. Combined expression of SOX10 and ANKRD55 have also been described as diagnostic (46; 105).

Genetics. These neoplasms show activation of the transcription factor FOXR2 by genomic structural rearrangements and gene fusions. FOXR2 plays a role in tumorigenesis and proliferation in several tumors, and its functional role for induction of CNS-embryonal neoplasms has been confirmed. In addition, nearly all tumors show 1q gain beside other copy number variations, such as 3p loss, 16q loss, and 17q gain (105).

Differential diagnosis

In poorly differentiated tumors, diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, CNS NB-FOXR2 is an important differential diagnosis and must be excluded. Extensive molecular testing is mandatory for the diagnosis of CNS NB-FOXR2. This may be focused on the identification of the FOXR2 alteration, eg, by RNA sequencing or by demonstration of the typical DNA methylation profile.

Imaging. FOXR2-activated CNS neuroblastoma usually appears as a large demarcated mass in a superficial cerebral hemisphere location with frequent areas of calcifications or hemorrhage. They may display a cystic or necrotic component but little edema. The solid component may show moderate and heterogeneous contrast enhancement, with low ADC values indicating high cellularity. Metastases are infrequent and, when present, are of nodular appearance and leptomeningeal (36; 32; 97).

Prognosis and outcomes

Retrospective analyses suggest that this group of tumors exhibit a good overall prognosis with 5-year overall survival rates of 80% or higher (46; 102). However, both local and distant relapses occur, and progression-free survival rates have been reported as 60% to 80%. Late relapses, occurring after 2 years and up to 5 years following initial diagnosis, have also been documented (32; 46; 102). Importantly, there were several survivors in the few reported patients with metastatic disease, justifying a curative treatment approach in cases with metastatic presentation (53; 102).

Management

Most of the reported patients with CNS NB-FOXR2 have received treatment according to diverse CNS PNET protocols (102; 59; 27). Data on the prognostic impact of staging at presentation are limited, and there is a lack of evidence on the prognostic relevance of postoperative residual tumor, with one retrospective study showing that it has no impact on survival (102).

Current data from the German group of 16 of 18 survivors who received craniospinal irradiation followed by chemotherapy suggest upfront craniospinal irradiation combined with chemotherapy according to former CNS PNET studies as the best treatment approach for children with CNS NB-FOXR2 tumors. Survivors treated with radiation-sparing approaches are anecdotal, and distant relapses are commonly seen in focally radiated patients (102; 59).

Infants and patients younger than 3 years of age with localized disease could benefit from a craniospinal irradiation-sparing regimen that consolidates with focal RT. Von Hoff and colleagues reported responses up to 60% to 70% in infants following chemotherapy and high-dose chemotherapy treatment, with effective use of salvage radiotherapy at relapse (102).

Overall, the number of reported patients with CNS NB-FOXR2 is very low. There is an urgent necessity for prospective registration and documentation of treatment and outcomes that may lead to prospective disease-tailored trials and the development of novel therapies.

CNS tumor with BCOR internal tandem duplication (BCOR-ITD)

This very rare embryonal brain tumor type is considered highly aggressive with poor survival within the limited cases reported so far (104).

Sturm and colleagues originally described a high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) (95). WHO CNS5 specified the diagnosis as CNS tumor with BCOR internal tandem duplication (CNS BCOR-ITD). These tumors are characterized by a distinct DNA methylation profile harboring specific genetic alterations in the exon 15 within the BCOR gene. There are insufficient data to assign a CNS WHO grade to this tumor with no consensus on whether these tumors should be considered mesenchymal or neuroepithelial neoplasms.

BCOR-ITD was previously detected in clear cell sarcomas of the kidney as well as soft tissue sarcoma (107; 108). Importantly, other aberrations within the BCOR gene have also been reported in other CNS tumors, which seem to play a role in the specific tumor biology but also do not qualify these tumors to be diagnosed as CNS tumor with BCOR-ITD (60; 70; 78; 07).

Epidemiology and clinical features

Fewer than 50 cases of CNS BCOR-ITD with clinical data have been reported in the literature. Like other rare embryonal tumors, they arise predominantly in young children (median age 4 years); however, cumulative cases have been reported in teenagers or young adults up to 22 years of age. Gender distribution is nearly balanced, with a male-to-female ratio of 0.8:1 (21; 10; 104). Primary tumors may arise across the entire CNS, with cerebral and cerebellar hemispheres being the most frequent locations and a slight predominance of an infratentorial location reported in the literature. Cases of primary basal ganglia and brainstem tumors have also been described (01; 21; 10). No patient with metastatic disease at presentation has been described. At relapse, leptomeningeal metastases, extracranial metastases, and direct invasion of surrounding tissues or along the neurosurgical access route have been observed (02; 43).

The clinical presentation is based on the location of the tumor and encompasses symptoms of raised intracranial pressure (eg, headache, vomiting, nausea, visual disturbances), focal neurologic deficits, ataxia, and seizures.

The limited case series available describe very poor prognosis with a median survival of 21 months (5-year overall survival less than 60%, 10-year overall survival less than 30%) and a propensity for early disease progression or recurrence (95; 21). Survival has not been associated with age, gender, or tumor location. Few cases with overall survival over 10 years have been reported (08; 21).

Pathology

CNS BCOR-ITD is a malignant CNS neoplasm generally demarcated at the interface with adjacent CNS parenchyma. It is characterized by a predominantly solid growth pattern, uniform oval or spindle-shaped cells with round to oval nuclei, characteristic focal pseudorosette formation, and an internal tandem duplication in exon 15 of the BCOR gene (53; 82). They may express focally OLIG2 but are generally negative for GFAP and synaptophysin. Immunohistochemically, expression of vimentin and CD56 is universal, and strong nuclear BCOR expression, albeit nonspecific, guides the diagnosis. The Ki-67 labeling index is elevated and ranges between 15% and 60%. For unresolved lesions, a DNA methylation profile aligned with CNS tumor with BCOR internal tandem duplication confirms the diagnosis.

Imaging

On MRI, CNS tumors with BCOR-ITD are typically intra-axial, very large, heterogeneous, and well-demarcated neoplasms of peripheral location abutting the overlying dura, involving multiple lobes and both cerebral hemispheres. Similarly to ETMR and FOX-R2 CNS tumors, they show restricted diffusion and weak contrast enhancement with no vasogenic edema, frequent central necrosis, hemorrhage, and calcifications. Despite the peripheral location adjacent to the dura, no dural tail sign or thickening of the dura mater, suggesting leptomeningeal dissemination, has been observed at the time of diagnosis (01; 21; 10).

Management

Optimal treatment strategies remain uncertain for this tumor entity. Most of the survivors reported in the literature benefited from gross total resection, which, regardless of the large tumor size at diagnosis, has been described to be amenable in most reported cases. Therefore, second surgery is highly advised in case of residual tumor.

Additional adjuvant therapy beyond the maximal safest resection possible should be strongly considered in all patients because rapid local recurrence and subsequent cerebrospinal dissemination have been observed in patients who did not receive adjuvant therapy.

Although the numbers are very small, it appears to be a trend for reduced relapses after upfront craniospinal irradiation (21; 104).

Focal or deferred radiation in younger patients could be considered following high-dose or conventional chemotherapy, including intraventricular chemotherapy to treat leptomeningeal dissemination in infants. There are anecdotal cases of survivors treated with radiation-sparing strategies (17; 53).

Different chemotherapy backbone regimens have been used in CNS BCOR-ITD tumors, mainly based on high-grade glioma and CNS embryonal tumor protocols (35).

Based on the presence of BCOR-ITD in several peripheral sarcomas, sarcoma tumor-type chemotherapy has also been proposed in CNS BCOR-ITD.

New drugs, like arsenic trioxide and ceritinib, have been shown to demonstrate anti-tumor activity in CNS BCOR-ITD in vitro and in vivo models (76; 75; 101).

No sufficient data establish a specific treatment strategy recommendation in this rare and aggressive entity. Regarding other rare CNS embryonal tumors of childhood, prospective collection of molecular and clinical tumor data and an individualized treatment approach in highly specialized pediatric neuro-oncology units is strongly advised.

A summary of molecular, clinical, radiological, and genomic features of rare embryonal brain tumors is shown in Table 2.

Pineoblastoma

Pineoblastoma is a malignant embryonal neoplasm of the pineal gland, WHO grade IV. Overall, pineal region tumors are considered rare entities, accounting for less than 1% of all CNS tumors. Pineoblastoma comprises 35% of all pineal parenchymal tumors with predilection for onset during the first two decades of life (30).

The rarity of pineoblastoma, similar to other rare embryonal neoplasms discussed in this article, has resulted in no clinical trials specifically conducted for this disease. Many patients with pineoblastoma succumb to their disease despite intensive cytotoxic chemotherapy and craniospinal radiotherapy, which is not feasible in young children.

Recent genome-wide DNA methylation studies have revealed that analogous to the vast majority of other CNS tumors, pineal parenchymal tumors are biologically heterogeneous and are composed of five core distinct molecular disease subgroups with unique clinical features and survival outcomes (55; 57; 77).

Epidemiology and clinical features

Pineoblastomas have generally been considered a disease of younger children; however, multi-institutional cooperative working groups demonstrated that patient demographics and disease features significantly differ across the pineoblastoma groups (Table 2). The median age at diagnosis is 6 years (range 0 to 41.5). Children under 3 years of age represent 24% to 28% of pineoblastomas, and younger age also has been associated with lower overall survival in several reports (58). Gender distribution is overall balanced but varies across different molecular groups, with a predominance of males in both PB-miRNA2 and PB-MYC/FOXR2 groups as described by Liu and colleagues in the pineoblastoma consensus study (58). Similarly to medulloblastoma, male gender has also been associated with worse EFS and overall survival in pineoblastoma, especially in younger patients. At presentation, 33% to 45% of pineoblastomas are metastatic; this also differs with molecular subtype, with 69% of the PB-RB group presenting as metastatic. Metastatic status in patients older than 3 years of age represents an adverse prognostic survival factor, whereas the prognosis remains dismal in younger patients regardless of the disease stage (28).

Table 2. Demographics and Clinical Features of Pineoblastoma Molecular Groups

	ETMR		CNS NB FOXR2	*CNS BCOR-ITD*	PINEOBLASTOMA
Molecular subgroups	C19MC altered	DICER altered	None	None	miRNA-1	miRNA-2	Myc/FOXR2 activated	RB1-altered
Gender distribution male:female	41%/59%		Balanced or slight predominance in females	Balanced	37%/63%	63%/37%	90%/30%	Balanced
Median age (range)	2 years (1.5-3 years)		5 years (1-20 years)	4 years (0.4 to 22 years)	8.5 years	11.6 years	1.3 years	2.1 years
Location	Supratentorial 65%, Infratentorial 35% (Brainstem 10%, Spinal 3%)		100% Supratentorial; cerebral hemispheres.	Peripheral cerebral and cerebellar hemispheres	Pineal gland
M stage	27% M+		17% M+	100% M0	40% M+	20% M+	60% M+	75% M+
MRI features	Large and multilobar, calcifications and cysts, no peripheral edema, low or no contrast enhancement, diffusion restriction.		Large demarcated mass in a superficial location. Cystic or necrotic component. Little edema, calcifications, or hemorrhagic areas. Moderate contrast enhancement, diffusion restriction.	Intra-axial, very large, heterogeneous, and well-demarcated neoplasms of peripheral location abutting the dura and involving multiple lobes. Diffusion restriction, weak contrast enhancement, no vasogenic edema, frequent necrosis, hemorrhage, and calcifications.	Large pineal tumors, frequently showing invasion of surrounding structures and hydrocephalus. Heterogeneous contrast enhancement and diffusion restriction.
Genomic or transcriptomic profile and cytogenetics	C19MC amplification. Cr2,1q,3q,7q,17q gains, Cr 6q losses	DICER1 mutations	FOXR2 activation 1q,17q gains,3p, 16q losses	BCOR-ITD (exon 15)	Copy number alterations, mutually exclusive mutations targeting DICER1M, DROSHA, or DGCR8.		MYC amplification, Cr 16q loss, FOXR2 overexpression.	RB-1 alterations
Cancer predisposition	None	DICER1 syndrome	None	None	DICER1 syndrome		None	Hereditary Retinoblastoma
Median overall survival	1.2 years		17.6 years	1.7 years	10.4 years	Not reached	1.2 years	2.8 years
Overall survival rate	(4 years) 27%		(5 years) 80%	(5 years) <60%	(5 years) 68%	(5 years)100%	(5 years) 23%	(5 years) 29%
PFS rate	(4 years) 31%		(5 years) 60%-80%	N/A	(5 years) 54%	(5 years) 93%	(5 years) 13%	(5 years) 27%
Abbreviations: CNS: central nervous system; NB: neuroblastoma; ITD: internal tandem duplication; M:metastatic; RB: retinoblastoma; EFS: event-free survival; N/A: not available.

Clinical vignette

A 2 month-old-boy was referred to an ophthalmologist due to leukocoria of his right eye noticed by his parents. Familial history was relevant for “congenital unilateral intraocular tumor” in his mother, treated with enucleation, and no further studies had been performed. Orbital MRI disclosed a large right intra-orbital mass occupying almost the entire vitreous chamber, consistent with retinoblastoma. MRI of the entire brain was otherwise normal at the time of diagnosis. Enucleation of the right eye was performed, and a genetic test revealed RB1 germline mutation, confirming the diagnosis of hereditary RB syndrome. Two months later, the infant presented with upward gaze palsy of his left eye. The parents reported noticing no other symptoms. Parinaud syndrome with vertical gaze palsy and nystagmus was confirmed on physical examination. Brain MRI revealed a large pineal mass, partially cystic and consistent with pineoblastoma and leptomeningeal dissemination to the entire neuroaxis. A diagnosis of trilateral familial retinoblastoma was established. Gross total resection was achieved, and intensive chemotherapy containing intraventricular methotrexate and intravenous vincristine, cyclophosphamide, cisplatin, etoposide, and methotrexate was delivered. However, the patient experienced rapid tumor progression and succumbed to the disease 8 months after he initial diagnosis of metastatic pineoblastoma.

Radiology features of metastatic trilateral familial retinoblastoma (RB-metastatic pineoblastoma)

(A) Axial MRI shows intraocular T2-hypointense tumor in the right eye. (B) T1 gadolinium sagittal view of the same patient at diagnosis, shows a large pineal mass, with mixed cystic and solid components, contrast-enhancing. (C)...

Pineoblastoma molecular groups

The German, Canadian, and North American Consensus molecular grouping in pineal parenchymal tumors by Liu and colleagues established four clinically and biologically relevant pineoblastoma groups and a fifth group corresponding to pineal parenchymal tumor of intermediate differentiation (58). Based on genome-wide DNA methylation profiling analysis, pineoblastoma groups are defined as PB-miRNA1 (43%), PB-miRNA2 (10%), PB-MYC/FOXR2 (15%), and PB-RB1 (11%), whereas pineal parenchymal tumor of intermediate differentiation represents 19% and affects mainly older patients. Demographics and clinical features of pineoblastoma groups are detailed in Table 2. Patients with PB-miRNA2, even with metastatic disease, have shown an excellent 5-year overall survival of 100%, whereas PB-miRNA1 patients exhibited intermediate outcomes with 5-year overall survival 70.3%. Patients with PB-MYC/FOXR2 and PB-RB1 had dismal outcomes, with respective 5-year overall survival of 19.2% and 29.8% (58).

Differential diagnosis

Although germ cell tumors account for nearly 50% to 75% of all primary pineal tumors, pineoblastomas represent the leading cause of primary pineal tumors in early childhood. In practice, the diagnosis of pineal region neoplasms is based on clinical presentation, imaging, and pathology results. Serum and CSF biomarkers to rule out germ cell tumors complement these standard diagnostic techniques by providing additional data before invasive procedures are performed (14; 36).

Pineoblastoma treatment

Role of surgery in pineoblastoma. Pineal tumors associated with acute and rapidly progressive hydrocephalus may be clinically managed via external ventriculostomy, endoscopic third ventriculostomy, ventriculoperitoneal shunts, or direct removal. Reflecting the challenge of surgery for pineal region tumors, only 38% to 47% of patients reported in the largest series benefited from gross total resection. The risk of hemorrhagic events, coupled with the small blood volume of infants and young children, and the pineal relationship to the deep cerebral veins, midbrain, and diencephalon are contributing factors that hinder complete surgical resections. Some reports have found gross total resection a positive prognosticator of survival in patients with pineoblastoma older than 3 years of age with nonmetastatic disease; however, evidence supporting the value of aggressive resection for patients with pineoblastoma is inconsistent with analysis reporting no association between gross total resection and improved outcomes (55; 57; 77; 28).

Chemotherapy and radiation. Historically, most children with pineoblastoma beyond infancy have received high-dose (36 Gy) craniospinal irradiation with multi-modal embryonal tumor-type chemotherapy, according to high risk medulloblastoma and sPNET protocols, regardless of the disease stage (79; 31). No particular embryonal brain tumor treatment strategy has demonstrated superior impact survival in pineoblastoma, with most available data mainly based on retrospective analysis nonspecifically designed for this rare tumor (20; 26). Five-year overall survival of 75% has been reported in older patients with pineoblastoma treated with different high-risk embryonal brain tumor protocols and 36 Gy craniospinal irradiation. This high rate of survival may be a reflection of the better outcomes associated with pineoblastoma group miRNA1 (5-year overall survival of 70.3%) and the excellent outcome in PB-miRNA2 (5-year overall survival of 100%) affecting older children (median age at diagnosis 8.5 years and 11.8 years respectively) (58). The encouraging results in PB-miRNA2, including survivors of focally radiated and metastatic pineoblastomas, may represent an opportunity to consider less intensive radiation regimens for this particular molecular group in future prospective trials. Based on these findings, in their consensus study Liu and colleagues proposed using 23.4 Gy of craniospinal irradiation in localized, totally resected miRNA1 and miRNA2 patients (58).

Infants and very young children with pineoblastoma have been mainly treated with radiation-sparing or delaying strategies and high-dose chemotherapy approaches, with some reports of nonradiated young long-term survivors who were recipients of high-dose chemotherapy (38; 37; 79; 31; 20; 26; 68; 36). Furthermore, the pooled analysis by Hansford and colleagues suggested that radiation therapy might not represent a positive prognosticator of survival in patients younger than 3 years of age with pineoblastoma (58). However, the lack of uniform criteria for radiation delivery in mostly retrospective small series of heterogeneously treated patients represents a major limitation in interpreting the role of radiotherapy in this age group. Moreover, underlying molecular characteristics with PB-MYC/FOXR2 and PB-RB1 groups enriched in younger patients (median age at diagnosis: 1.4 years and 2.1 years, respectively) may negate any underlying prognostic factors (58).

The dose and extent of radiation as well as its impact on survival in this extremely vulnerable population remains uncertain. Furthermore, radiotherapy deferral approaches might be impractical due to the short time to progression in pineoblastoma. Proton therapy focal radiation to infant pineoblastoma represents a less toxic radiation option that should be explored in future prospective trials (40). Localized and metastatic infant pineoblastomas can be considered ultra-high-risk diseases with dismal prognoses for which the development of novel therapeutic strategies is urgently needed. Importantly, the impact of specific treatments on patient survival in the context of the newly recognized molecular groups of pineoblastoma has yet to be evaluated.

References

01: Al-Battashi A, Al Hajri Z, Perry A, Al-Kindi H, Al-Ghaithi I. A cerebellar high-grade neuroepithelial tumour with BCOR alteration in a five-year-old child: a case report. Sultan Qaboos Univ Med J 2019;19(2):e153-6. PMID 31538015
02: Appay R, Macagno N, Padovani L, et al. HGNET-BCOR tumors of the cerebellum: clinicopathologic and molecular characterization of 3 cases. Am J Surg Pathol 2017;41(9):1254-60. PMID 28704208
03: Balzeau J, Menezes MR, Cao S, Hagan JP. The LIN28/let-7 pathway in cancer. Front Genet 2017;8:31. PMID 28400788
04: Bartelheim K, Nemes K, Seeringer A, et al. Improved 6-year overall survival in AT/RT: results of the registry study Rhabdoid 2007. Cancer Med 2016;5(8):1765-75. PMID 27228363
05: Bhadarge PS, Datar SS, Umap PS, Shrivastava AC. Primitive neuroectodermal tumor presenting as a presacral mass: a rare case report with review of literature. Indian J Pathol Microbiol 2017;60(2):250-2. PMID 28631646
06: Bode U, Zimmermann M, Moser O, et al. Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial. J Neurooncol 2014;120(3):635-42. PMID 25179451
07: Bouchoucha Y, Tauziède-Espariat A, Gauthier A, et al. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family. J Pathol Clin Res 2022;8(3):217-32. PMID 35174661
08: Bremer J, Kottke R, Johann PD, et al. A single supratentorial high-grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival. Pediatr Blood Cancer 2020;67(7):e28384. PMID 32383815
09: Cao D, Liu A, Wang F, et al. RNA-binding protein LIN28 is a marker for primary extragonadal germ cell tumors: an immunohistochemical study of 131 cases. Mod Pathol 2011;24(2):288-96. PMID 21057460
10: Cardoen L, Tauziède-Espariat A, Dangouloff-Ros V, et al. Imaging features with histopathologic correlation of CNS high-grade neuroepithelial tumors with a BCOR internal tandem duplication. AJNR Am J Neuroradiol 2022;43(1):151-6. PMID 34887247
11: Chadda K, Solano-Paez P, Khan S, et al. Embryonal tumor with multilayered rosettes: overview of diagnosis and therapy. Neuroonc Adv 2023;5(1):1-7. PMID 37727849
12: Cohen BH, Geyer JR, Miller DC, et al. Pilot study of intensive chemotherapy with peripheral hematopoietic cell support for children less than 3 years of age with malignant brain tumors, the CCG-99703 Phase I/II Study: a report from the Children's Oncology Group. Pediatr Neurol 2015;53(1):31-46. PMID 26092413
13: Cohen BH, Packer RJ, Siegel KR, et al. Brain tumors in children under 2 years: treatment, survival and long-term prognosis. Pediatr Neurosurg 1993;19:171-9. PMID 8329301
14: Dai AI, Backstrom JW, Burger PC, Duffner PK. Supratentorial primitive neuroectodermal tumors of infancy: clinical and radiologic findings. Pediatr Neurol 2003;29(5):430-4. PMID 14684239
15: Dangouloff-Ros V, Tauziède-Espariat A, Roux CJ, et al. CT and multimodal MR imaging features of embryonal tumors with multilayered rosettes in children. AJNR Am J Neuroradiol 2019;40(4):732-36. PMID 30846437
16: de Kock L, Sabbaghian N, Druker H, et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 2014;128(4):583-95. PMID 25022261
17: De Lima L, Sürme MB, Gessi M, et al. Central nervous system high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)-case-based reviews. Childs Nerv Syst 2020;36(8):1589-99. PMID 32542405
18: Duffner PK, Cohen ME. Long-term consequences of CNS treatment for childhood cancer, Part II: clinical consequences. Pediatr Neurol 1991;7(4):237-42. PMID 1930413
19: Eberhart CG, Brat DJ, Cohen KJ, Burger PC. Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol 2000;3(4):346-52. PMID 10890250
20: Fangusaro J, Finlay J, Sposto R, et al. Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 2008;50(2):312-8. PMID 17668858
21: Ferris SP, Velazquez Vega J, Aboian M, et al. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol 2020;30(1):46-62.** PMID 31104347
22: Finlay JL. The role of high-dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors: a reappraisal. Pediatr Transplant 1999;3 Suppl 1:87-95. PMID 10587977
23: Francis SS, Ostrom QT, Cote DJ, Smith TR, Claus E, Barnholtz-Sloan JS. The epidemiology of central nervous system tumors. Hematol Oncol Clin North Am 2022;36(1):23-42. PMID 34801162
24: Gerber NU, von Hoff K, von Bueren AO, et al. Outcome of 11 children with ependymoblastoma treated within the prospective HIT-trials between 1991 and 2006. J Neurooncol 2011;102(3):459-69. PMID 21308398
25: Gessi M, Giangaspero F, Lauriola L, et al. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol 2009;33(2):211-7. PMID 18987548
26: Gilheeney SW, Saad A, Chi S, et al. Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy. J Neurooncol 2008;89(1):89-95. PMID 18415046
27: Gojo J, Kjaersgaard M, Zezschwitz BV, et al. Rare embryonal and sarcomatous central nervous system tumors: state of the art and future directions. Eur J Med Genet 2023;66(1):1004660. PMID 36356895
28: Hansford JR, Huang J, Endersby R, et al. Pediatric pineoblastoma: a pooled outcome study of North American and Australian therapeutic data. Neurooncol Adv 2022;4(1):vdac056.** PMID 35664557
29: Hanson D, Hoffman LM, Nagabushan S, et al. A modified IRS-III chemotherapy regimen leads to prolonged survival in children with embryonal tumor with multilayer rosettes. Neurooncol Adv 2020;2(1):vdaa120. PMID 33196040
30: Hasselblatt M, Huang A, Jones DT. Pineal tumors: Pineoblastoma. In: WHO Classification of Tumors of the Central Nervous System Tumours. 5th Ed. Vol 6. Lyon (France) International Agency for Research on Cancer, 2021.**
31: Hinkes BG, von Hoff K, Deinlein F, et al. Childhood pineoblastoma: experiences from the prospective multicenter trials HIT-SKK87, HIT-SKK92 and HIT91. J Neurooncol 2007;81(2):217-23. PMID 16941074
32: Holsten T, Lubieniecki F, Spohn M, et al. Detailed clinical and histopathological description of 8 cases of molecularly defined CNS neuroblastomas. J Neuropathol Exp Neurol 2021;80(1):52-9. PMID 33270865
33: Honnorat M, Al-Karmi S, Hawkins C, et al. Presacral medulloepithelioma: case report and literature review. J Pediatr Hematol Oncol 2020;42(3):244-7. PMID 30994507
34: Horwitz M, Dufour C, Leblond P, et al. Embryonal tumors with multilayered rosettes in children: the SFCE experience. Childs Nerv Syst 2016;32(2):299-305. PMID 26438544
35: Hwang EI, Kool M, Burger PC, et al. Extensive molecular and clinical heterogeneity in patients with histologically diagnosed CNS-PNET treated as a single entity: a report from the Children's Oncology Group Randomized ACNS0332 Trial. J Clin Oncol 2018;36(34):JCO2017764720. PMID 30332335
36: Jaju A, Hwang EI, Kool M, et al. MRI features of histologically diagnosed supratentorial primitive neuroectodermal tumors and pineoblastomas in correlation with molecular diagnoses and outcomes: a report from the Children's Oncology Group ACNS0332 Trial. AJNR Am J Neuroradiol 2019;40(11):1796-803. PMID 31601576
37: Jakacki RI, Burger PC, Kocak M, et al. Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 2015;62(5):776-83. PMID 25704363
38: Jakacki RI, Zeltzer PM, Boyett JM, et al. Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 1995;13(6):1377-83. PMID 7751882
39: Jaramillo S, Grosshans DR, Philip N, et al. Radiation for ETMR: literature review and case series of patients treated with proton therapy. Clin Transl Radiat Oncol 2018;15:31-37. PMID 30582019
40: Jazmati D, Steinmeier T, Ahamd Khalil D, et al. Feasibility of proton beam therapy for infants with brain tumours: experiences from the Prospective KiProReg Registry Study. Clin Oncol (R Coll Radiol) 2021;33(7):e295-304. PMID 33820696
41: Juhnke BO, Gessi M, Gerber NU, et al. Treatment of embryonal tumors with multilayered rosettes with carboplatin/etoposide induction and high-dose chemotherapy within the prospective P-HIT trial. Neuro Oncol 2022;24(1):127-37.** PMID 33908610
42: Khan S, Solano-Paez P, Suwal T, et al. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study. Lancet Child Adolesc Health 2021;5(11):800-813.** PMID 34599879
43: Kirkman MA, Pickles JC, Fairchild AR, et al. Early wound site seeding in a patient with central nervous system high-grade neuroepithelial tumor with BCOR alteration. World Neurosurg 2018;116:279-84. PMID 29859355
44: Korshunov A; Fuller GN, Haberler C, et al. Embryonal tumour with multilayered rossettes. In: WHO Classification of Tumors of the Central Nervous System Tumours. 5th Ed. Vol 6. Lyon (France) International Agency for Research on Cancer, 2021a.**
45: Korshunov A, Jakobiec FA, Eberhart CG, et al. Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities. Neuropathology 2015;35(6):538-44. PMID 26183384
46: Korshunov A, Okonechnikov K, Schmitt-Hoffner F, et al. Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation. Acta Neuropathol Commun 2021b;9(1):20. PMID 33536079
47: Korshunov A, Remke M, Gessi M, et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 2010;120(2):253-60. PMID 20407781
48: Korshunov A, Sturm D, Ryzhova M, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol 2014;128(2):279-89. PMID 24337497
49: Lambo S, Gröbner SN, Rausch T, et al. The molecular landscape of ETMR at diagnosis and relapse. Nature 2019;576(7786):274-80. PMID 31802000
50: Lambo S, von Hoff K, Korshunov A, Pfister SM, Kool M. ETMR: a tumor entity in its infancy. Acta Neuropathol 2020;140(3):249-66. PMID 32601913
51: Lang SS, Beslow LA, Gabel B, et al. Surgical treatment of brain tumors in infants younger than six months of age and review of the literature. World Neurosurg 2012;78(1-2):137-44. PMID 22120270
52: Lassaletta A, Lopez-Ibor B, Mateos E, et al. Intrathecal liposomal cytarabine in children under 4 years with malignant brain tumors. J Neurooncol 2009;95(1):65-9. PMID 19381444
53: Lastowska M, Trubicka J, Sobocińska A, et al. Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes. Acta Neuropathol Commun 2020;8(1):105. PMID 32650833
54: Levine A, Hukin J, Dunham C. Pontine embryonal tumor with multilayered rosettes: an autopsy case exhibiting extensive posttreatment glial and neuronal maturation. Pediatr Dev Pathol 2020;23(4):326-31. PMID 32282273
55: Li BK, Vasiljevic A, Dufour C, et al. Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study. Acta Neuropathol 2020;139(2):223-41. PMID 31820118
56: Li M, Lee KF, Lu Y, et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 2009;16(6):533-46. PMID 19962671
57: Liu AP, Gudenas B, Lin T, et al. Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials. Acta Neuropathol 2020;139(2):259-71. PMID 31802236
58: Liu AP, Li BK, Pfaff E, et al. Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study. Acta Neuropathol 2021;141(5):771-85.** PMID 33619588
59: Liu AP, Dhanda SK, Lin T, et al. Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials. Acta Neuropathol 2022;144(4):733-46. PMID 35982322
60: Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 2017;32(4):520-37.e5. PMID 28966033
61: Manjila S, Ray A, Hu Y, Cai DX, Cohen ML, Cohen AR. Embryonal tumors with abundant neuropil and true rosettes: 2 illustrative cases and a review of the literature. Neurosurg Focus 2011;30(1):E2. PMID 21194275
62: Manoranjan B, Provias JP. Congenital brain tumors: diagnostic pitfalls and therapeutic interventions. J Child Neurol 2011;26(5):599-614. PMID 21464236
63: Mayr L, Gojo J, Peyrl A, et al. ETMR-10. Early focal radiotherapy and temozolomide following complete resection appear superior to intensive chemotherapy and delayed radiotherapy in children with embryonal tumors with multilayered rossettes (ETMR). Volume 22. Issue Supplement_3.Neuro-Oncology, 2020a:iii324-5.
64: Mayr L, Gojo J, Peyrl A, et al. Potential importance of early focal radiotherapy following gross total resection for long-term survival in children with embryonal tumors with multilayered rosettes. Front Oncol 2020b;10:584681. PMID 33392079
65: Mazewski C, Kang G, Kellie S, Gossett J, Leary S, Li B, Aridgides P, Hayes L, Reddy A, Shaw D, Burger P, Judkins A, Geyer JR, Fouladi M, Huang A. ETMR-20. Impact of high dose chemotherapy with and without methotrexate (MTX) on outcome of patients with embryonal tumors with multi-layered rosettes (etmrs): a report from Children’s Oncology Group Phase III Trial ACNS0334. Neuro Oncol 2020;22(Suppl 3):iii327.
66: McKean-Cowdin R. Head circumference at birth linked to cancer in childhood. Lancet Oncol 2006;7(1):4-5. PMID 16389174
67: McKean-Cowdin R, Razavi P, Barrington-Trimis J, et al. Trends in childhood brain tumor incidence, 1973-2009. J Neurooncol 2013;115(2):153-60. PMID 23925828
68: Mynarek M, Pizer B, Dufour C, et al. Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. Neuro Oncol 2017;19(4):576-85. PMID 28011926
69: Nobusawa S, Orimo K, Horiguchi K, et al. Embryonal tumor with abundant neuropil and true rosettes with only one structure suggestive of an ependymoblastic rosette. Pathol Int 2014;64(9):472-7. PMID 25186165
70: Northcott PA, Buchhalter I, Morrissy AS, et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017;547(7663):311-7. PMID 28726821
71: O'Neil SH, Whitaker AM, Kayser K, et al. Neuropsychological outcomes on Head Start III: a prospective, multi-institutional clinical trial for young children diagnosed with malignant brain tumors. Neurooncol Pract 2020;7(3):329-37. PMID 32537181
72: Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol 2022;24(Suppl 5):v1-95. PMID 36196752
73: Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro Oncol 2020;22(12 Suppl 2):iv1-96. PMID 33123732
74: Pajtler KW, Tippelt S, Siegler N, et al. Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors. J Neurooncol 2016;128(3):463-71. PMID 27147083
75: Paret C, Russo A, Otto H, et al. Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy. Oncotarget 2017;8(69):114210-25. PMID 29371980
76: Paret C, Theruvath J, Russo A, et al. Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy. Oncotarget 2016;7(50):83378-91. PMID 27825128
77: Pfaff E, Aichmüller C, Sill M, et al. Molecular subgrouping of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations. Acta Neuropathol 2020;139(2):243-257. PMID 31768671
78: Pisapia DJ, Ohara K, Bareja R, et al. Fusions involving BCOR and CREBBP are rare events in infiltrating glioma. Acta Neuropathol Commun 2020;8(1):80. PMID 32493417
79: Pizer BL, Weston CL, Robinson KJ, et al. Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer 2006;42(8):1120-8. PMID 16632346
80: Pompe RS, von Bueren AO, Mynarek M, et al. Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy. Eur J Cancer 2015;51(17):2634-42. PMID 26346136
81: Ramaswamy V, Remke M, Shih D, et al. Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent. Pediatr Blood Cancer 2014;61(7):1190-4. PMID 24616042
82: Rao S, Mitra S, Sugur H, et al. Central nervous system high grade neuroepithelial tumor with BCOR immunopositivity: Is there a molecular heterogeneity? Brain Tumor Pathol 2021;38(1):41-9. PMID 32980923
83: Rao S, Rajeswarie RT, Chickabasaviah Yasha T, Nandeesh BN, Arivazhagan A, Santosh V. LIN28A, a sensitive immunohistochemical marker for Embryonal Tumor with Multilayered Rosettes (ETMR), is also positive in a subset of Atypical Teratoid/Rhabdoid Tumor (AT/RT). Childs Nerv Syst 2017;33(11):1953-9. PMID 28744687
84: Robert-Boire V, Desnous B, Lortie A, et al. Seizures in pediatric patients with primary brain tumors. Pediatr Neurol 2019;97:50-5. PMID 31036424
85: Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005;352(10):978-86. PMID 15758008
86: Sandberg DI, Rytting M, Zaky W, et al. Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. J Neurooncol 2015;125(1):133-41. PMID 26255071
87: Sato H, Terakawa Y, Tsuyuguchi N, Kuwae Y, Ohsawa M, Ohata K. Embryonal tumor with abundant neuropil and true rosettes in the brainstem: case report. J Neurosurg Pediatr 2015;16(3):291-5. PMID 26090549
88: Schmidt C, Schubert NA, Brabetz S, et al. Preclinical drug screen reveals topotecan, actinomycin D, and volasertib as potential new therapeutic candidates for ETMR brain tumor patients. Neuro Oncol 2017;19(12):1607-1617. PMID 28482026
89: Schultz KA, Williams GM, Kamihara J, et al. DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res 2018;24(10):2251-61. PMID 29343557
90: Shah AH, Khatib Z, Niazi T. Extracranial extra-CNS spread of embryonal tumor with multilayered rosettes (ETMR): case series and systematic review. Childs Nerv Syst 2018;34(4):649-54. PMID 29177676
91: Sin-Chan P, Li BK, Ho B, Fonseca A, Huang A. Molecular classification and management of rare pediatric embryonal brain tumors. Curr Oncol Rep 2018;20(9):69. PMID 29995179
92: Sin-Chan P, Mumal I, Suwal T, et al. A C19MC-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs: a lethal brain tumor. Cancer Cell 2019;36(1):51-67.e7. PMID 31287992
93: Slavc I, Schuller E, Falger J, et al. Feasibility of long-term intraventricular therapy with mafosfamide (n = 26) and etoposide (n = 11): experience in 26 children with disseminated malignant brain tumors. J Neurooncol 2003;64(3):239-47. PMID 14558599
94: Spence T, Sin-Chan P, Picard D, et al. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol 2014;128(2):291-303. PMID 24839957
95: Sturm D, Orr BA, Toprak UH, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016;164(5):1060-72.** PMID 26919435
96: Sung KW, Lim DH, Lee SH, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age. J Neurooncol 2012;107(2):335-42. PMID 22081297
97: Tietze A, Mankad K, Lequin MH, et al. Imaging characteristics of CNS neuroblastoma-FOXR2: a retrospective and multi-institutional description of 25 cases. AJNR Am J Neuroradiol 2022;43(10):1476-80. PMID 36137662
98: Tsai ML, Chen CL, Hsieh KL, et al. Seizure characteristics are related to tumor pathology in children with brain tumors. Epilepsy Res 2018;147:15-21. PMID 30176531
99: Tsialikas J, Romer-Seibert J. LIN28: roles and regulation in development and beyond. Development 2015;142(14):2397-404. PMID 26199409
100: Uro-Coste E, Masliah-Planchon J, Siegfried A, et al. ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors. Acta Neuropathol 2019;137(1):175-77. PMID 30446821
101: Vewinger N, Huprich S, Seidmann L, et al. IGF1R is a potential new therapeutic target for HGNET-BCOR brain tumor patients. Int J Mol Sci 2019;20(12):3027. PMID 31234291
102: von Hoff K, Haberler C, Schmitt-Hoffner F, et al. Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study. Neuro Oncol 2021;23(9):1597-611.** PMID 34077956
103: Wang B, Gogia B, Fuller GN, Ketonen LM. Embryonal tumor with multilayered rosettes, C19MC-altered: clinical, pathological, and neuroimaging findings. J Neuroimaging 2018;28(5):483-9. PMID 29797626
104: Wang R, Guan W, Qiao M, et al. CNS tumor with BCOR internal tandem duplication: clinicopathologic, molecular characteristics and prognosis factors. Pathol Res Pract 2022;236:153995.** PMID 35809497
105: Wesseling P, Haberler C, Huang A, et al. CNS neuroblastoma, FOXR2-activated. In: WHO Classification of Tumors of the Central Nervous System. 5th Ed. Vol 6. Lyon (France) International Agency for Research on Cancer, 2021a.**
106: Wesseling P, Pfister SM, et al. Other CNS embryonal tumors. In: WHO Classification of Tumors of the Central Nervous System. 5th Ed. Vol 6. Lyon (France) International Agency for Research on Cancer, 2021b.**
107: Wong MK, Ng CCY, Kuick CH, et al. Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion. Histopathology 2018;72(2):320-9. PMID 28833375
108: Yoshida Y, Nobusawa S, Nakata S, et al. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol 2018;28(5):710-20. PMID 29226988
109: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Palma Solano Páez MD

Dr. Solano Páez of Hospital Infantil Virgen el Rocio in Seville has no relevant financial relationships to disclose.
See Profile
Adriana Fonseca MD

Dr. Fonseca Sheridan of Children's National Hospital and George Washington University has no relevant financial relationships to disclose.
See Profile

Editor

Roger J Packer MD

Dr. Packer of Children’s National Medical Center and George Washington University has no relevant financial relationships to disclose.
See Profile

Former Authors

Roger J Packer MD

ICD & OMIM codes

ICD-11: Other specified embryonal tumours of brain: 2A00.1Y

Embryonal tumours of brain, unspecified: 2A00.1Z
ICD-O: ETMR: 9478/3

CNS NB FOXR2 Activated: 9500/3

CNS tumor with BCOR internal tandem duplication: 9500/3

PINEOBLASTOMA: 9362/3

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Rare brain embryonal tumors in infancy and early childhood

Differential Diagnosis

low- or high-grade glial or neuronal tumors
atypical teratoid/rhabdoid tumor
malignant gliomas
neurodegenerative processes
uncontrolled seizures
- infantile spasms
- congenital hydrocephalus
- acquired hydrocephalus
- nonprogressive encephalopathies
- cerebral palsy
- failure to thrive due to noncentral nervous system conditions
- spasmus nutans
- intracranial neoplasms
- hydrocephalus
- macrocephaly
- uniocular nystagmus
- torticollis

Also Relevant

Atypical teratoid/rhabdoid tumors
Brainstem gliomas in childhood
Cerebellar astrocytoma
Choroid plexus tumors of childhood
Ependymoma
- Medulloblastoma
- Optic pathway gliomas
- Radiation: CNS complications

Clinical Categories

General Child Neurology

Patient Handouts

Web References

Clinical Trials

NCI: Pediatric Oncology

Rare brain embryonal tumors in infancy and early childhood

Introduction

Overview

Key points

Historical note and terminology

Table 1. Embryonal Brain Tumors of Infant and Young Children

Clinical manifestations

Presentation and course

Embryonal tumor with multilayered rosettes (ETMR)

Prognosis and complications

Clinical vignette

Biological basis

C19MC alteration and DICER1 mutation drive genetic aberrations in ETMR

Pathology

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

CNS neuroblastoma, FOXR2-activated

Epidemiology and clinical features

Pathology

Differential diagnosis

Prognosis and outcomes

Management

CNS tumor with BCOR internal tandem duplication (BCOR-ITD)

Epidemiology and clinical features

Pathology

Imaging

Management

Pineoblastoma

Epidemiology and clinical features

Table 2. Demographics and Clinical Features of Pineoblastoma Molecular Groups

Clinical vignette

Pineoblastoma molecular groups

Differential diagnosis

Pineoblastoma treatment

Special considerations

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Breath-holding spells

Acute cerebellar ataxia in children

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Zika virus: neurologic complications

Cerebral edema in childhood

This is an article preview.
Start a Free Account
to access the full version.