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 (12). Many rare embryonal tumors are believed to be congenital, and they present during times of maximum brain growth and development (64; 60). 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 (79).

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 (44; 104). 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 (24; 40). CNS BCOR-ITD shows an equal preference for peripheral location both in the cerebral and cerebellar hemispheres (20; 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 (67; 85; 52).

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 (88; 20; 40). Not surprisingly, brainstem location and metastatic disease are both adverse prognostic factors, with only a few reported survivors (40). Seventeen percent of CNS NB FOXR2 are metastatic at diagnosis (100). 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 (20). 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 (32). 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% (32).

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 (64); 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 (96); furthermore, young age was found to be inversely related to the onset of seizures in children with a brain tumor in a multivariate analysis (82). 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 (18). 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 (54; 46). These studies led to the designation of C19MC-altered ETMRs, which were initially included as a new entity in WHO CNS4 in 2016 (93). 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 (98; 42). 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 (24; 32; 40), 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.

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 (24; 54).

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 (54; 45). 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 (98). 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 (47). 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 (47; 48).

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 (97). 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 (90). 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; 92; 81). 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 (43).

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 (39).

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 (15; 56).

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; 31).

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 (48).

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 (15; 56) and ciliary body medulloepithelioma (87; 31).

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 (101; 14; 34).

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 (49).

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 (64). 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 (32). 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 (40). 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 (39). 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 (67; 85; 52; 40).

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 (100). 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 (27). 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 (86).

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 (83; 84). However, methotrexate is a neurotoxic agent that can add significant acute and long-term side effects to this vulnerable and heavily treated population (17; 69). Remarkably, preliminary results of the ACNS0334 protocol observed no difference in survival by methotrexate randomization in the subset of fourteen enrolled patients with ETMRs (63). 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 (61). Similarly, in the French cohort, a long-term survivor with a totally resected ETMR was treated with temozolomide and irinotecan, followed by craniospinal radiotherapy (32).

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 (21; 94; 06; 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%) (39). 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 (40). 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 (32).

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 (32; 72; 62; 40) 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 (39).

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 (40).

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 (23; 59; 32; 37). However, based on the pattern of ETMR progression and relapses predominantly observed locally (32; 62; 40) 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 (27; 61; 40; 39).

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 (32; 40; 39). 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 (62). 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 (91; 83; 50; 78; 04; 72). 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 (24).

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 (39). 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 (27). 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 (62). 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 (86) 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 (78; 72).

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 (93).

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 (93; 44; 100; 57). Only supratentorial CNS NB-FOXR2 tumors have been reported, with most cases arising from the cerebral hemispheres and some anecdotal reports of intraventricular location (93; 30). CNS metastases have been reported in up to 17% of cases (100).

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 (44; 103).

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 (103).

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 (34; 30; 95).

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 (44; 100). 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 (30; 44; 100). Importantly, there were several survivors in the few reported patients with metastatic disease, justifying a curative treatment approach in cases with metastatic presentation (51; 100).

Management

Most of the reported patients with CNS NB-FOXR2 have received treatment according to diverse CNS PNET protocols (100; 57). 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 (100).

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 (100; 57).

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 (100).

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 (102).

Sturm and colleagues originally described a high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) (93). 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 (105; 106). 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 (58; 68; 76; 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 (20; 10; 102). 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; 20; 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; 41).

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 (93; 20). Survival has not been associated with age, gender, or tumor location. Few cases with overall survival over 10 years have been reported (08; 20).

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 (51; 80). 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; 20; 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 (20; 102).

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 (16; 51).

Different chemotherapy backbone regimens have been used in CNS BCOR-ITD tumors, mainly based on high-grade glioma and CNS embryonal tumor protocols (33).

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 (74; 73; 99).

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 (28).

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 (53; 55; 75).

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 (56). 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 (56). 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 (26).

Table 2. Demographics and Clinical Features of Pineoblastoma Molecular Groups

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.

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 (56). 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% (56).

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 (13; 34).

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 (53; 55; 75; 26).

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 (77; 29). 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 (19; 25). 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) (56). 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 (56).

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 (36; 35; 77; 29; 19; 25; 66; 34). 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 (56). 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 (56).

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 (38). 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.

Special considerations

Anesthesia

Precautions similar to those for any patient with increased intracranial pressure due to obstructive hydrocephalus should be undertaken.