Molecular subtypes of nonmedulloblastoma embryonal tumors

Cribriform neuroepithelial tumor: Representing less than 50% of nonmedulloblastoma embryonal tumors, this subtype is a nonrhabdoid tumor that arises in the vicinity of the third, fourth, or lateral ventricles. This tumor is characterized by cribriform strands and ribbons and demonstrates loss of nuclear SMARCB1 expression. The median age at diagnosis is 20 months. This tumor occurs more often in males, with a male-to-female ratio of 1.5 to 1.[85]Genomic characterization of ten cases of cribriform neuroepithelial tumors showed large heterozygous 22q deletions in nine of ten cases with SMARCB1 variants on the alternative allele.[85] Cribriform neuroepithelial tumor showed DNA methylation profiles that matched those of the TYR subtype of atypical teratoid/rhabdoid tumor (AT/RT), a tumor that also arises in young children and shows loss of SMARCB1 expression. Patients with cribriform neuroepithelial tumors appear to have relatively favorable outcomes, in contrast to those of patients with AT/RT-TYR.[85]

Embryonal tumor with multilayered rosettes (ETMR): Representing up to 20% of nonmedulloblastoma embryonal tumors, this subtype combines embryonal, rosette-forming, neuroepithelial brain tumors that were previously categorized as either embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, or medulloepithelioma.[28,145] ETMRs arise most commonly in young children (median age at diagnosis, 2–3 years) but may occur in older children.[144-149] ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[145,150,151] This gene fusion puts expression of C19MC under control of the TTYH1 promoter, leading to high-level aberrant expression of the microRNAs within the cluster. The World Health Organization (WHO) allows histologically similar tumors without C19MC alteration to be classified as ETMR, not otherwise specified (NOS). This subclass of tumors without C19MC alterations may harbor biallelic DICER1 variants.

Central nervous system (CNS) neuroblastoma with FOXR2 activation (CNS NB-FOXR2): Representing 10% to 15% of nonmedulloblastoma embryonal tumors, this tumor may occur in children younger than 3 years, but it more frequently occurs in older children. This subtype is characterized by genomic alterations that lead to increased expression of the transcription factor FOXR2.[28] CNS NB-FOXR2 is primarily observed in children younger than 10 years, and the histology of these tumors is typically that of CNS neuroblastoma or CNS ganglioneuroblastoma.[28,152] There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple FOXR2 partners identified.[28] Protein expression of SOX10 and ANKRD55 detected by immunohistochemistry has been proposed as a potential biomarker to differentiate CNS NB-FOXR2 tumors from related tumor types.[152]

CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR): Representing up to 3% of nonmedulloblastoma embryonal tumors, this subtype is characterized by internal tandem duplications of BCOR,[28] a genomic alteration that is also found in clear cell sarcoma of the kidney.[153,154] While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur.[28]

CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC): Representing 2% to 4% of nonmedulloblastoma embryonal tumors, this subtype is characterized by genomic alterations affecting CIC (located on chromosome 19q13.2), with fusion to NUTM1 being identified in several cases tested.[28,144] CIC gene fusions are also identified in extra-CNS Ewing-like sarcomas, and the gene expression signature of CNS EFT-CIC tumors is similar to that of these sarcomas.[28] CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology.[28]

CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1): Representing 1% to 3% of nonmedulloblastoma embryonal tumors, this subtype is characterized by gene fusions involving MN1 (located on chromosome 22q12.3), with fusion partners including BEND2 and CXXC5.[28,144] The CNS HGNET-MN1 subtype shows a striking female predominance, and it tends to occur in the second decade of life.[28] This subtype contained most cases carrying a diagnosis of astroblastoma per the 2007 WHO classification scheme.[28] This subtype has not been added to the WHO diagnostic lexicon. Two other reports that together examined 35 cases of histologically defined astroblastoma found that 14 showed methylation profiles consistent with CNS HGNET-MN1 and/or MN1 alterations by fluorescence in situ hybridization.[29,30]

Medulloepithelioma: Medulloepithelioma with the classic C19MC amplification is considered an ETMR, C19MC-altered (see the ETMR information above). However, when a tumor has the histological features of medulloepithelioma, but without a C19MC amplification, it is still identified as an ETMR.[155,156] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[155,156] Intraocular medulloepithelioma is biologically distinct from intra-axial medulloepithelioma.[157,158]

CNS embryonal tumor with PLAGL amplification: A retrospective analysis of more than 90,000 pediatric and adult brain tumors identified a small subset of embryonal tumors (n = 31) with distinct methylation profiles and high-level amplification and overexpression of either PLAGL1 or PLAGL2.[159] Additional recurrent genetic alterations observed in other pediatric CNS tumor types were not observed in these cases. These tumors occurred throughout the brain and were most commonly composed of primitive embryonal-like cells without markers of glial or neuronal differentiation. In this small cohort, differences in age at diagnosis and 10-year overall survival (OS) rates were reported between patients with PLAGL1 amplification (median age, 10.5 years; OS rate, 66%) and patients with PLAGL2 amplification (median age, 2 years; OS rate, 25%).