Childhood Cancer Genomics (PDQ®), part 2

The malignant cells of Burkitt lymphoma show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin (Ig), most bearing a clonal surface IgM with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt lymphomas express CD10.[1]

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Burkitt lymphoma expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYC oncogene and the immunoglobulin locus (IG, mostly the IGH locus) regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[2,3] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[4,5]

Sources: 2 · 3 · 4 · 5

Mapping of IGH-translocation breakpoints demonstrated that IG::MYC translocations in sporadic Burkitt lymphoma most commonly occur through aberrant class-switch recombination and less commonly through somatic hypervariant. Translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare.[6] These findings are consistent with a germinal center derivation of Burkitt lymphoma.

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While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Some of the more commonly observed recurring variants that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these variants for pediatric Burkitt lymphoma remains to be elucidated.

A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of variants for endemic and sporadic cases and for EBV-positive and EBV-negative cases. However, EBV-positive cases showed significantly lower variant rates for selected genes/pathways, including SMARCA4, CCND3, TP53, and apoptosis.[5]

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Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma and has no clinical implications.[12]

Sources: 1 · 12

Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.[13] In the 5th edition of the WHO classification, this entity was renamed high-grade B-cell lymphoma with 11q aberrations.[14] In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[15,16]

Sources: 13 · 14 · 15 · 16

For information about the treatment of childhood Burkitt lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

Gene expression profiling of diffuse large B-cell lymphoma in adults has defined molecular subtypes. These subtypes are based on the suspected cell of origin, including germinal center B cell (GCB), activated B cell (ABC), and 10% to 15% of cases that remain unclassifiable. Current comprehensive molecular profiling of diffuse large B-cell lymphoma in adults has led to the proposal of additional subclassification beyond the cell of origin. This additional subclassification is based on genetic variants and copy number variations.[18,19] Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

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Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a distinct entity in the 5th edition of the WHO classification of lymphoid neoplasms.[28]

Sources: 28

High-grade B-cell lymphoma, NOS, is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements. In addition, this entity does not meet criteria for diffuse large B-cell lymphoma, NOS, or Burkitt lymphoma.[33]

Sources: 33

For information about the treatment of childhood diffuse large B-cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the World Health Organization (WHO) classification.[14] These tumors arise in the mediastinum from thymic B cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

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Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

Primary mediastinal B-cell lymphoma has distinctive gene expression and variant profiles compared with diffuse large B-cell lymphoma. However, its gene expression and variant profiles have features similar to those seen in Hodgkin lymphoma.[35-37] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.

Sources: 35 · 37

For information about the treatment of childhood primary mediastinal B-cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase. More than 75% of cases have a T-cell immunophenotype and the remaining cases have a precursor B-cell phenotype.[49]

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As opposed to pediatric T-cell acute lymphoblastic leukemia (T-ALL), the molecular biology and chromosomal abnormalities of pediatric lymphoblastic lymphoma are not as well characterized. Many genomic alterations that occur in T-ALL also occur in T-cell lymphoblastic lymphoma. Examples include the following:

For the genomic alterations described above, NOTCH1 and FBXW7 variants may confer a more favorable prognosis for patients with T-cell lymphoblastic lymphoma. In contrast, loss of heterozygosity at chromosome 6q, PTEN variants, and KMT2D variants may be associated with an inferior prognosis.[51-55] For example, one study noted that the presence of a KMT2D and/or PTEN variant was associated with a high risk of relapse in patients with wild-type NOTCH1 or FBXW7, but these variants were not associated with an increased risk of relapse in patients with variants in NOTCH1 or FBXW7.[54] Studies with larger numbers of patients are needed to better define the critical genomic determinants of outcome for patients with T-cell lymphoblastic lymphoma.

Sources: 51 · 55 · 54

A distinctive genomic subtype of T-cell lymphoblastic lymphoma is characterized by gene fusions involving NOTCH1. TRB is the most common fusion partner. This subtype is absent, or extremely rare, in T-ALL.

Among 192 pediatric patients with T-cell lymphoblastic lymphoma, 12 cases (6.3%) had TRB::NOTCH1 gene fusions. These fusions were not identified in the 167 cases of T-ALL. Features of the 12 patients with TRB::NOTCH1 fusions included the following:[56]

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A second study identified NOTCH1 gene fusions in 6 of 29 (21%) pediatric patients with T-cell lymphoblastic lymphoma. The specific gene fusions were miR142::NOTCH1 (n = 2), TRBJ::NOTCH1 (n = 3), and IKZF2::NOTCH1 (n = 1).[57]

Sources: 57

There have been few studies of the genomic characteristics of B-cell lymphoblastic lymphoma. One report described copy number alterations for pediatric B-cell lymphoblastic lymphoma cases. The study noted that some gene deletions that are common in B-ALL (e.g., CDKN2A, IKZF1, and PAX5) appeared to occur with appreciable frequency in B-cell lymphoblastic lymphoma.[58]

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The morphology and immunophenotype of B-cell lymphoblastic lymphoma are known to overlap with those of B-ALL, but few studies have examined the genomic landscape of B-cell lymphoblastic lymphoma, partially due to the lack of sufficient material for genomic analysis.[58] One study has better evaluated the genomic alterations associated with pediatric B-cell lymphoblastic lymphoma.[59] The study analyzed 97 cases of B-cell lymphoblastic lymphoma using a combination of targeted DNA, whole-exome, and RNA sequencing. Overall, the results showed remarkable similarities in the variant and transcriptional landscape between B-cell lymphoblastic lymphoma and B-ALL.

Sources: 58 · 59

For information about the treatment of childhood lymphoblastic lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

While mature T cell is the predominant immunophenotype of anaplastic large cell lymphoma, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[14,60]

Sources: 14 · 60

All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the NPM::ALK fusion protein. The other 15% of cases are composed of variant ALK translocations.[61] The anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM::ALK fusion proteins, whereas cytoplasmic staining of ALK is only associated with the variant ALK translocations, as shown in Table 4.[62]

Sources: 61 · 62

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In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[63] Also, adult patients with ALK-negative anaplastic large cell lymphoma have an inferior outcome compared with patients who have ALK-positive disease.[64] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[65-67]

Sources: 63 · 64 · 65 · 67

One European series included 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma. The presence of a small cell or lymphohistiocytic component was observed in 32% of patients, and it was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[66] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite using a different chemotherapy backbone.[67]

Sources: 66 · COG-ANHL0131 · 67

For information about the treatment of childhood anaplastic large cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

Pediatric-type follicular lymphoma and nodal marginal zone lymphoma are rare indolent B-cell lymphomas that are clinically and molecularly distinct from these tumor types in adults.

For information about the treatment of pediatric-type follicular lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.

Sources: Childhood Non-Hodgkin Lymphoma Treatment

Classical Hodgkin lymphoma has a molecular profile that differs from that of non-Hodgkin lymphomas. The exception is primary mediastinal B-cell lymphoma, which shares many genomic and cytogenetic characteristics with Hodgkin lymphoma.[1,2] Characterization of genomic alterations for Hodgkin lymphoma is challenging because malignant Hodgkin and Reed-Sternberg (HRS) cells make up only a small percentage of the overall tumor mass. Because of this finding, special methods, such as microdissection of HRS cells or flow cytometry cell sorting, are required before applying molecular analysis methods.[2-5] Hodgkin lymphoma genomic alterations can also be assessed using special sequencing methods applied to circulating cell-free DNA (cfDNA) in peripheral blood of patients with Hodgkin lymphoma.[6,7]

Sources: 1 · 2 · 2 · 5 · 6 · 7

The genomic alterations observed in Hodgkin lymphoma fall into several categories, including immune evasion alterations, JAK-STAT pathway alterations, alterations leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation, and others:

The lymphocyte-predominant (LP) cells of NLPHL have distinctive genomic characteristics compared with the HRS cells of Hodgkin lymphoma. As with Hodgkin lymphoma, genomic characterization is complicated by the low percentage of malignant cells within a tumor mass.

For information about the treatment of childhood Hodgkin lymphoma, see Childhood Hodgkin Lymphoma Treatment.

Sources: Childhood Hodgkin Lymphoma Treatment

Central nervous system (CNS) tumors include gliomas (including astrocytomas), glioneuronal tumors, neuronal tumors, CNS atypical teratoid/rhabdoid tumors, medulloblastomas, nonmedulloblastoma embryonal tumors, pineal tumors, and ependymomas.

The terminology of the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System is used below. The 2021 WHO CNS classification advances the role of molecular diagnostics in CNS tumor classification, and it includes multiple major changes from the previous 2016 WHO classification.[1]

Sources: 1

This category includes, among other diagnoses, pediatric-type diffuse low-grade gliomas, pediatric-type diffuse high-grade gliomas, circumscribed astrocytic gliomas, glioneuronal tumors, and neuronal tumors.

For pediatric-type diffuse gliomas, rearrangements in the MYB family of transcription factors (MYB and MYBL1) are the most commonly reported genomic alteration in low-grade tumors.[2-4] Other alterations observed include FGFR1 alterations (primarily duplications involving the tyrosine kinase domain),[3,4] BRAF alterations, NF1 variants, and RAS family variants.[2,3] IDH1 variants, which are the most common genomic alteration in adult-type diffuse astrocytomas, are uncommon in children with diffuse astrocytomas and, when present, are observed almost exclusively in older adolescents.[2,5]

Sources: 2 · 4 · 3 · 4 · 2 · 3 · 2 · 5

The diffuse midline glioma, H3 K27M-altered, category includes tumors previously classified as diffuse intrinsic pontine glioma (DIPG). Most of the data is derived from experience with DIPG. This category also includes gliomas with the H3 K27M variant arising in midline structures such as the thalamus.

Children with NF1 have an increased propensity to develop low-grade gliomas, especially in the optic pathway. Up to 20% of patients with NF1 will develop an optic pathway glioma. Most children with NF1-associated optic nerve gliomas are asymptomatic and/or have nonprogressive symptoms and do not require antitumor treatment. Screening magnetic resonance imaging (MRI) in asymptomatic patients with NF1 is usually not indicated, although some investigators perform baseline MRI for young children who cannot undergo detailed ophthalmologic examinations.[6]

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The diagnosis is often based on compatible clinical findings and imaging features. Histological confirmation is rarely needed at the time of diagnosis. When biopsies are performed, these tumors are predominantly pilocytic astrocytomas.[7]

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Indications for treatment vary and are often based on the goal of preserving vision.

Very rarely, patients with NF1 develop high-grade gliomas. Sometimes, this tumor is the result of a transformation of a lower-grade tumor.[8]

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Patients with tuberous sclerosis have a predilection for developing subependymal giant cell astrocytoma (SEGA). Variants in either TSC1 or TSC2 cause constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, leading to increases in proliferation. SEGAs are responsive to molecularly targeted approaches with mTORC1 pathway inhibitors.[9][Level of evidence C2] Patients with tuberous sclerosis are also at risk of developing cortical tubers and subependymal nodules.

Sources: 9 · Level of evidence C2

Recurrent genomic alterations resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, most commonly involving the BRAF gene, represent the primary (and often sole) oncogenic driver in the vast majority of pediatric low-grade gliomas, including pilocytic/pilomyxoid astrocytomas, gangliogliomas, and others.[7] As a result, most of these tumors are amenable to molecular targeted therapies.

Sources: 7

More complex tumor genomes are characteristic of pediatric diffuse high-grade gliomas. These complex genomes include recurrent genomic alterations in the H3 histone encoding genes (e.g., H3F3A, HIST1H3B), DNA damage repair pathways (e.g., TP53, PPM1D, ATM, MDM2), chromatin modifiers (e.g., ATRX, BCOR, SETD2), cell cycle pathways (e.g., CDKN2A, CDKN2B, RB1), and/or oncogene amplifications (PDGFR, VEGFR2, KIT, MYC, MYCN).[10] For most of these tumors, existing conventional and molecular targeted therapies have limited efficacy.

Sources: 10

A rare subset of pediatric high-grade gliomas arising in patients with inheritable biallelic mismatch repair deficiency (bMMRD) is characterized by an extraordinarily high mutational burden. Correctly identifying these patients at the time of diagnosis is critical because of intrinsic resistance to temozolomide and responsiveness to treatment with immune checkpoint inhibitors.[11][Level of evidence C3]; [12]

Sources: 11 · Level of evidence C3 · 12

BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF::KIAA1549 gene fusion, resulting in a fusion protein that lacks the BRAF autoregulatory domain.[13] This fusion is seen in most infratentorial and midline pilocytic astrocytomas but is present at lower frequency in supratentorial (hemispheric) tumors.[7]

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Presence of the BRAF::KIAA1549 fusion is associated with improved clinical outcome (progression-free survival [PFS] and overall survival [OS]) in patients with pilocytic astrocytoma.[14]; [15][Level of evidence C1] Progression to high-grade gliomas is very rare for pediatric gliomas with the BRAF::KIAA1549 fusion.[15]

Sources: 14 · 15 · Level of evidence C1 · 15

Activating single nucleotide variants in BRAF, most commonly BRAF V600E, are present in a subset of pediatric gliomas and glioneuronal tumors across a wide spectrum of histologies, including pleomorphic xanthoastrocytoma, pilocytic astrocytoma, ganglioglioma, desmoplastic infantile ganglioglioma/astrocytoma, and others.[7] Some low-grade, infiltrative, pediatric gliomas with an alteration in a MAPK pathway gene, including BRAF, and often resembling diffuse low-grade astrocytoma or oligodendroglioma histologically, are now classified as diffuse low-grade glioma, MAPK pathway altered.[1,16]

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Retrospective clinical studies have shown the following:

Somatic alterations in NF1 are seen most frequently in children with NF1 and are associated with germline alterations in the tumor suppressor NF1. Loss of heterozygosity for NF1 represents the most common somatic alteration in these patients followed by inactivating variants in the second NF1 allele, and consistent with a second hit required for tumorigenesis. While most NF1 patients with low-grade gliomas have an excellent long-term prognosis, secondary transformation into high-grade glioma may occur in a small subset. Genomically, transformation is associated with the acquisition of additional oncogenic drivers, such as loss of function alterations in CDKN2A, CDKN2B and/or ATRX. Primary high-grade gliomas may also occur in patients with NF1 but are exceedingly rare. Genomic alterations involving the MAPK signaling pathway other than NF1 are very uncommon in gliomas occurring in children with NF1.[8]

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High-grade gliomas with distinctive molecular characteristics arise in infants, typically in those diagnosed during the first year of life.[19-21] These tumors are characterized by recurrent oncogenic gene fusions involving ALK, NTRK1, NTRK2, NTRK3, or ROS1 as the primary and, typically, sole oncogenic driver. Infants with this type of glioma, now classified as infant-type hemispheric glioma, have a much better prognosis compared with older children with high-grade gliomas. Remarkably, these tumors may evolve from high-grade to low-grade histology over time, and it remains unclear how much this phenomenon is a consequence of natural disease history versus treatment-induced changes.[19]

Sources: 19 · 21 · 19

ROS1 gene fusions have also been reported in gliomas occurring in older children and adults. A retrospective meta-analysis that included 40 children older than 1 year revealed that ROS1 gene fusions occurred in diverse glioma histologies, including diffuse high-grade and low-grade gliomas and glioneuronal tumors.[21] Similar to ROS1-altered cases occurring in infants, tumor variants in other known driver genes were rare. However, tumor copy number alterations were more frequent in older children than infants.

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As an alternative to BRAF activation or NF1 loss, other primary oncogenic driver alterations along the MAPK signaling pathway have been observed in pilocytic astrocytomas and other pediatric-type gliomas. These include oncogenic variants and/or fusions involving FGFR1, FGFR2, PTPN11, RAF1, NTRK2, and others.[4,7,22]

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Low-grade gliomas with rearrangements in the MYB family of transcription factors [2,3,7] have been classified as a separate entity: diffuse astrocytoma, MYB- or MYBL1-altered, WHO grade 1.[1] Prognosis is generally favorable for patients with these tumors, particularly when a gross-total resection or near-total resection is obtained at the time of surgery.[23]

Sources: 2 · 3 · 7 · 1 · 23

Angiocentric gliomas typically arise in children and young adults as cerebral tumors presenting with seizures.[24]

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Two reports in 2016 identified MYB gene alterations as being present in almost all cases diagnosed as angiocentric glioma, with QKI being the primary fusion partner in cases where fusion-partner testing was possible.[4,25] While angiocentric gliomas most commonly occur supratentorially, brain stem angiocentric gliomas with MYB::QKI fusions have also been reported.[26,27]

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Astroblastomas are defined histologically as glial neoplasms composed of GFAP-positive cells and contain astroblastic pseudorosettes that often demonstrate sclerosis. Astroblastomas are diagnosed primarily in childhood through young adulthood.[24]

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The following studies have described genomic alterations associated with astroblastoma:

These reports suggest that the histological diagnosis of astroblastoma encompasses a heterogeneous group of genomically defined entities. Astroblastomas with MN1 fusions represent a distinctive subset of histologically diagnosed cases.[32]

Sources: 32

IDH1- and IDH2-altered tumors occur in the pediatric population as low-grade gliomas (WHO Grade 2), high-grade gliomas (WHO Grade 3 and 4), and oligodendrogliomas with codeletion of 1p and 19q. For more information about IDH1- and IDH2-altered gliomas, see the IDH1 and IDH2 variants section in the Molecular features of pediatric-type high-grade gliomas section.

Sources: IDH1 and IDH2 variants

Pediatric high-grade gliomas are biologically distinct from those arising in adults.[5,33-35]

Sources: 5 · 33 · 35

Pediatric-type high-grade gliomas can be separated into distinct subgroups based on epigenetic patterns (DNA methylation). These subgroups show distinguishing chromosome copy number gains/losses and gene variants in the tumor.[10,36,37] Particularly distinctive subtypes of pediatric high-grade gliomas are those with recurring variants at specific amino acids in histone genes, and together these account for approximately one-half of pediatric high-grade gliomas.[10]

Sources: 10 · 36 · 37 · 10

The following pediatric-type high-grade glioma subgroups were identified based on their DNA methylation patterns, and they show distinctive molecular and clinical characteristics:[10]

Sources: 10

The histone K27–altered cases occur predominantly in middle childhood (median age, approximately 10 years), are almost exclusively midline (thalamus, brain stem, and spinal cord), and carry a very poor prognosis. The 2021 WHO classification groups these cancers into a single entity: diffuse midline glioma, H3 K27-altered. However, there are clinical and biological distinctions between cases with H3.3 and H3.1 variants, as described below.[1]

Sources: 1

Diffuse midline glioma, H3 K27-altered, is defined by loss of H3 K27 trimethylation either due to an H3 K27M variant or, less commonly, overexpression of EZHIP. This entity includes most high-grade gliomas located in the thalamus, pons (diffuse intrinsic pontine gliomas [DIPGs]), and spinal cord, predominantly in children, but also in adults.[38]

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H3.3 K27M: H3.3 K27M cases occur throughout the midline and pons, account for approximately 60% of cases in these locations, and commonly present between the ages of 5 and 10 years.[10] The prognosis for H3.3 K27M patients is especially poor, with a median survival of less than 1 year; the 2-year survival rate is less than 5%.[10] Leptomeningeal dissemination is frequently observed in H3.3 K27M patients.[39]

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H3.1 K27M: H3.1 K27M cases are approximately fivefold less common than H3.3 K27M cases. They occur primarily in the pons and present at a younger age than other H3.3 K27M patients (median age, 5 years vs. 6–10 years). These patients have a slightly more favorable prognosis than do H3.3 K27M patients (median survival, 15 months vs. 11 months). Variants in ACVR1, which is also the variant observed in the genetic condition fibrodysplasia ossificans progressiva, are present in a high proportion of H3.1 K27M cases.[10,40,41]

Sources: 10 · 40 · 41

H3.2 K27M: Rarely, K27M variants are also identified in H3.2 (HIST2H3C) cases.[10]

Sources: 10

A subset of tumors with H3 K27 variants will have a BRAF V600E or FGFR1 co-variant.[42] A retrospective cohort of 29 tumors combined with 31 cases previously reported in the literature demonstrated a somewhat higher propensity for a thalamic location. These cases exhibit a unique DNA methylation cluster that is distinct from other diffuse midline glioma subgroups and glioma subtypes with BRAF or FGFR1 alterations. The median survival for these patients exceeded 3 years.[43] A separate retrospective study of pediatric and adult patients with H3 K27-altered gliomas revealed BRAF V600E variants in 5.8% (9 of 156) and FGFR1 variants in 10.9% (17 of 156) of patients younger than 20 years.[44] Other recurrent genetic alterations detected in pediatric patients included variants in TP53, ATRX, PIK3CA, and amplifications of PDGFRA and KIT. FGFR1 variants were noted to be more frequent in patients older than 20 years (31.8%, 47 of 148).

Sources: 42 · 43 · 44

EZHIP overexpression: The small minority of patients with diffuse midline gliomas lacking histone H3 variants often show EZHIP overexpression.[38] EZHIP inhibits PRC2 activity, leading to the same loss of H3 K27 trimethylation that is induced by H3 K27M variants.[45] Overexpression of EZHIP is likewise observed in posterior fossa type A ependymomas, which also shows loss of H3 K27 methylation.[46]

Sources: 38 · 45 · 46

The H3.3 G34 subtype arises from H3.3 glycine 34 to arginine/valine (G34R/V) variants.[36,37] This subtype presents in older children and young adults (median age, 14–18 years) and arises exclusively in the cerebral cortex.[36,37] H3.3 G34 cases commonly have variants in TP53 and ATRX (95% and 84% of cases, respectively, in one large series) and show widespread hypomethylation across the whole genome. In a series of 95 patients with the H3.3 G34 subtype, 44% of patients also had a variant in PDGFRA at the time of diagnosis, and 81% of patients had PDGFRA variants observed at relapse.[47]

Sources: 36 · 37 · 36 · 37 · 47

Patients with H3F3A variants are at high risk of treatment failure,[48] but the prognosis is not as poor as that of patients with histone 3.1 or 3.3 K27M variants.[37] O-6-methylguanine-DNA methyltransferase (MGMT) methylation is observed in approximately two-thirds of cases, and aside from the IDH1-altered subtype (see below), the H3.3 G34 subtype is the only pediatric high-grade glioma subtype that demonstrates MGMT methylation rates exceeding 20%.[10]

Sources: 48 · 37 · 10

IDH1- and IDH2-altered tumors occur in the pediatric population as low-grade gliomas (WHO grade 2), high-grade gliomas (WHO grades 3 and 4), and oligodendrogliomas with codeletion of 1p and 19q.[49]

Sources: 49

IDH1-altered cases represent a small percentage of high-grade gliomas (approximately 5%–10%) seen in pediatrics, and are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors.[10,49] These tumors are classified under adult-type diffuse glioma, as astrocytoma, IDH-altered in the 2021 WHO CNS classification. IDH1-altered cases often show TP53 variants, MGMT promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP).[36,37]

Sources: 10 · 49 · 36 · 37

Pediatric patients with IDH1 variants have a more favorable prognosis than patients with other types of high-grade gliomas.[10] A retrospective multi-institutional review of pediatric patients with IDH-altered gliomas and available outcome data (n = 76) reported a 5-year PFS rate of 44% (95% CI, 25%–59%) and a 5-year OS rate of 92% (95% CI, 79%–97%).[49] Approximately 25% of the gliomas in the cohort were classified as high grade. There was no difference in 5-year PFS rates observed between tumor grades. However, patients with high-grade tumors had a worse 5-year OS rate of 75% (95% CI, 40%–91%).

Sources: 10 · 49

Rare, IDH-altered, high-grade gliomas have been reported to occur in children with mismatch repair–deficiency syndromes (Lynch syndrome or constitutional mismatch repair deficiency syndrome).[50] These tumors, termed primary mismatch repair–deficient IDH-altered astrocytomas (PMMRDIAs), could be distinguished from other IDH-altered gliomas by methylation profiling. PMMRDIAs have molecular features that are distinct from most IDH-altered gliomas, including a hypervariant phenotype and frequent activation of receptor tyrosine kinase pathways. Patients with PMMRDIAs have a markedly worse prognosis than patients with other IDH-altered gliomas, with a median survival of 15 months.

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Approximately 10% of pediatric high-grade gliomas have DNA methylation patterns that are PXA-like.[37] PXA-like cases commonly have BRAF V600E variants and a relatively favorable outcome (approximately 50% survival at 5 years).[10,48]

Sources: 37 · 10 · 48

This entity was included in the 2016 WHO classification (called pilocytic astrocytoma with anaplasia) to describe tumors with histological features of pilocytic astrocytoma, increased mitotic activity, and additional high-grade features. The current nomenclature was adopted in the 2021 WHO classification. A more recent publication described a cohort of 83 cases with these histological features (referred to as anaplastic astrocytoma with piloid features) that shared a common DNA methylation profile, which is distinct from the methylation profiles of other gliomas. These tumors occurred more often in adults (median age, 41 years), and they harbored frequent deletions of CDKN2A/B, MAPK pathway alterations (most often in the NF1 gene), and variants or deletions of ATRX. They are associated with a clinical course that is intermediate between pilocytic astrocytoma and IDH–wild-type glioblastoma.[51]

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Pediatric patients with glioblastoma multiforme high-grade glioma whose tumors lack both histone variants and IDH1 variants represent approximately 40% of pediatric glioblastoma multiforme cases.[10,52] This is a heterogeneous group, with higher rates of gene amplifications than other pediatric high-grade glioma subtypes. The most commonly amplified genes are PDGFRA, EGFR, CCND/CDK, and MYC/MYCN.[36,37] MGMT promoter methylation rates are low in this group.[52] One report divided this group into three subtypes. The subtype characterized by high rates of MYCN amplification showed the poorest prognosis, while the subtype characterized by TERT promoter variants and EGFR amplification showed the most favorable prognosis. The third group was characterized by PDGFRA amplification.[52]

Sources: 10 · 52 · 36 · 37 · 52 · 52

Infants and young children with high-grade gliomas appear to have tumors with distinctive molecular characteristics [19,20] when compared with tumors of older children and adults with high-grade gliomas. An indication of this difference was noted with the application of DNA methylation analysis to pediatric high-grade tumors, which found that approximately 7% of pediatric patients with a histological diagnosis of high-grade glioma had tumors with methylation patterns more closely resembling those of low-grade gliomas.[10] Ten of 16 infants (younger than 1 year) with a high-grade glioma diagnosis were in this methylation array–defined group.[10] The 5-year survival rate for patients in this report diagnosed at younger than 1 year exceeded 60%, while the 5-year survival rate for patients aged 1 to 3 years and older was less than 20%.

Sources: 19 · 20 · 10 · 10

Two studies of the molecular characteristics of high-grade gliomas in infants and young children have further defined the distinctive nature of tumors arising in children younger than 1 year. A key finding from both studies is the importance of gene fusions involving tyrosine kinases (e.g., ALK, NTRK1, NTRK2, NTRK3, and ROS1) in patients in this age group. Both studies also found that infants with high-grade gliomas whose tumors have these gene fusions have survival rates much higher than those of older children with high-grade gliomas.[19,20]

Sources: 19 · 20

The first study presented data for 118 children younger than 1 year with a low-grade or high-grade glioma diagnosis who had tumor tissue available for genomic characterization.[19] Approximately 75% of the cases were classified as low grade, but the diminished utility of histological classification in this age group was illustrated by the relatively low OS rate for the low-grade cohort (71%) and the relatively favorable survival for the high-grade cohort (55%). Rates of surgical resection were higher for patients with high-grade tumors, a result of many of the low-grade tumors occurring in midline locations while the high-grade tumors were found in supratentorial locations. This finding may also help to explain the relative outcomes for the two groups. Genomic characterization divided the infant glioma population into the following three groups, the first of which included patients with high-grade gliomas:

Sources: 19

The second study focused on tumors from children younger than 4 years with a pathological diagnosis of WHO grades 2, 3, and 4 gliomas, astrocytomas, or glioneuronal tumors. Among the 191 tumors studied that met inclusion criteria, 61 had methylation profiles consistent with glioma subtypes that occur in older children (e.g., IDH1, diffuse midline glioma H3 K27-altered, SEGA, pleomorphic xanthoastrocytoma, etc.). The remaining 130 cases were called the intrinsic set and were the focus of additional molecular characterization:[20]

Sources: 20

Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF::KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E variants were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E variants, with CDKN2A alterations present in 8 of 14 cases (57%).[15]

Sources: 15

Glioneuronal and neuronal tumors are generally low-grade tumors. Select histologies recognized by the 2021 WHO classification include the following:[1]

Sources: 1

Ganglioglioma presents during childhood and into adulthood. It most commonly arises in the cerebral cortex and is associated with seizures, but it also presents in other sites, including the spinal cord.[53,54]

Sources: 53 · 54

The unifying theme for the molecular pathogenesis of ganglioglioma is genomic alterations leading to MAPK pathway activation.[4,55] BRAF alterations are observed in approximately 50% of ganglioglioma cases, with V600E being by far the most common alteration. However, other BRAF variants and gene fusions are also observed. Other less commonly altered genes in ganglioglioma include KRAS, FGFR1, FGFR2, RAF1, NTRK2, and NF1.[4,55]

Sources: 4 · 55 · 4 · 55

DIA and DIG most often present in the first year of life and show a characteristic imaging appearance in which a contrast-enhancing solid nodule accompanies a large cystic component.[56,57] DIG is more common than DIA,[56] and by methylation array analysis, both diagnoses cluster together.[58] Survival outcome is generally favorable with surgical resection.[56]

Sources: 56 · 57 · 56 · 58 · 56

The most commonly observed genomic alterations in DIA and DIG are BRAF variants involving V600. Gene fusions involving kinase genes are observed less frequently.

DNET presents in children and adults, with the median age at diagnosis in mid-to-late adolescence. It is characterized histopathologically by the presence of columns of oligodendroglial-like cells and cortical ganglion cells floating in mucin.[61] The temporal lobe is the most common location, and it is associated with drug-refractory epilepsy.[54,62]

Sources: 61 · 54 · 62

FGFR1 alterations have been reported in 60% to 80% of DNETs, and include FGFR1 activating single nucleotide variants, internal tandem duplication of the kinase domain, and activating gene fusions.[4,63,64] BRAF variants are uncommon in DNET.

Sources: 4 · 63 · 64

Papillary glioneuronal tumor is a low-grade biphasic neoplasm with astrocytic and neuronal differentiation that primarily arises in the supratentorial compartment.[24] The median age at presentation is in the early 20s, but it can be observed during childhood through adulthood.

Sources: 24

The primary genomic alteration associated with papillary glioneuronal tumor is a gene fusion, SLC44A1::PRKCA, that is associated with the t(9:17)(q31;q24) translocation.[65,66] In one study of 28 cases diagnosed histologically as papillary glioneuronal tumor using methylation arrays, 11 of the cases clustered in a distinctive methylation class, while the remaining cases showed methylation profiles typical for other tumor entities. Molecular analysis of the cases in the distinctive methylation cluster showed that all of them had the SLC44A1::PRKCA gene fusion except for a single case with a NOTCH1::PRKCA gene fusion.[67] This suggests that molecular methods for identifying the presence of a PRKCA fusion are less susceptible to misclassification in diagnosing papillary glioneuronal tumor than are morphology-based methods.

Sources: 65 · 66 · 67

RGNT presents in adolescents and adults, with tumors generally located infratentorially, although tumors can arise in mesencephalic or diencephalic regions.[68] The typical histological appearance shows both a glial component and a neurocytic component arranged in rosettes or perivascular pseudorosettes.[24] Outcome for patients with RGNT is generally favorable, consistent with the WHO grade 1 designation.[68]

Sources: 68 · 24 · 68

DNA methylation profiling shows that RGNT has a distinct epigenetic profile that distinguishes it from other low-grade glial/glioneuronal tumor entities.[68] A study of 30 cases of RGNT observed FGFR1 hotspot variants in all analyzed tumors.[68] In addition, PIK3CA activating variants were concurrently observed in 19 of 30 cases (63%). Missense or damaging variants in NF1 were identified in 10 of 30 cases (33%), with 7 tumors having variants in FGFR1, PIK3CA, and NF1. The co-occurrence of variants that activate both the MAPK pathway and the PI3K pathway makes the variant profile of RGNT distinctive among astrocytic and glioneuronal tumors.

Sources: 68 · 68

DLGNT is a rare CNS tumor that has been characterized radiographically by leptomeningeal enhancement on MRI that may involve the posterior fossa, brain stem region, and spinal cord.[69] Intraparenchymal lesions, when present, typically involve the spinal cord.[69] Localized intramedullary glioneuronal tumors without leptomeningeal dissemination and with histomorphological, immunophenotypic, and genomic characteristics similar to DLGNT have been reported.[70]

Sources: 69 · 69 · 70

DLGNT showed a distinctive epigenetic profile on DNA methylation arrays, and unsupervised clustering of array data applied to 30 cases defined two subclasses of DLGNT: methylation class (MC)-1 (n = 17) and MC-2 (n = 13).[69] Of note, many of the array-defined cases had originally been diagnosed as other entities (e.g., primitive neuroectodermal tumors, pilocytic astrocytoma, and anaplastic astrocytoma). Patients with DLGNT-MC-1 were diagnosed at an earlier age than were patients with DLGNT-MC-2 (5 years vs. 14 years, respectively). The 5-year OS rate was higher for patients with DLGNT-MC-1 than for those with DLGNT-MC-2 (100% vs. 43%, respectively). Genomic findings from the 30 cases of methylation array–defined DLGNT are provided below:

Sources: 69

Extraventricular neurocytoma is histologically similar to central neurocytoma, consisting of small uniform cells that demonstrate neuronal differentiation. However, extraventricular neurocytoma arises in the brain parenchyma rather than in association with the ventricular system.[24] It presents during childhood through adulthood.

Sources: 24

In a study of 40 tumors histologically classified as extraventricular neurocytoma and subjected to methylation array analysis, only 26 formed a separate cluster distinctive from reference tumors of other histologies.[72] Among cases with an extraventricular neurocytoma methylation array classification for which genomic characterization could be performed, 11 of 15 (73%) showed rearrangements affecting members of the FGFR family, with FGFR1::TACC1 being the most common alteration.[72]

Sources: 72 · 72

For information about the treatment of gliomas, glioneuronal tumors, and neuronal tumors, see Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment.

Sources: Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment

AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1, was identified.[73] SMARCB1 is genomically altered in most rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[73] SMARCB1 is a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex.[74]

Sources: 73 · 73 · 74

Rare cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 variants have also been associated with somatic or germline variants of SMARCA4, another member of the SWI/SNF chromatin-remodeling complex.[75-77]

Sources: 75 · 77

Less commonly, SMARCA4-negative (with retained SMARCB1) tumors have been described.[75-77] Loss of SMARCB1 or SMARCA4 staining is a defining marker for AT/RT.

Sources: 75 · 77

The 2021 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumors with rhabdoid features.[78]

Sources: 78

Despite the absence of recurring genomic alterations beyond SMARCB1 and SMARCA4,[79-81] biologically, relatively distinctive subsets of AT/RT have been identified.[82-84] In one study, three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:[83]

Sources: 79 · 81 · 82 · 84 · 83

Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity.[88] Preclinical studies have shown that some AT/RT xenograft lines with SMARCB1 loss respond to EZH2 inhibitors with tumor growth inhibition and occasional tumor regression.[89,90] In a study of the EZH2 inhibitor tazemetostat, objective responses were observed in adult patients whose tumors had either SMARCB1 or SMARCA4 loss (non-CNS malignant rhabdoid tumors and epithelioid sarcoma).[91] For more information, see the Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section.

Sources: 88 · 89 · 90 · 91 · Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor

For information about the treatment of childhood CNS AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment.

Sources: Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment

Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[92-115] Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes, including WNT-activated, sonic hedgehog (SHH)–activated, group 3, and group 4. In the 2021 World Health Organization (WHO) classification, the SHH subgroup has been divided into two groups based on TP53 status. Group 3 and group 4, which require methylation analysis for reliable separation, have been combined into medulloblastoma, non-WNT/non-SHH. Because the group 3 and group 4 terminology has been used extensively in completed studies and is still in use in ongoing and planned studies, this nomenclature will be maintained throughout the clinical discussion in this summary.[1,78]

Sources: 92 · 115 · 1 · 78

Different regions of the same tumor are likely to have other disparate genetic variants, adding to the complexity of devising effective molecularly targeted therapy.[110] However, the major subtypes noted above remain stable across primary and metastatic components.[111,114]

Sources: 110 · 111 · 114

Further subclassification within these subgroups is possible, which will provide even more prognostic information.[112-114]

Sources: 112 · 114

WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[112] WNT medulloblastomas show a WNT signaling gene expression signature and beta-catenin nuclear staining by immunohistochemistry.[116] They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. WNT medulloblastomas generally occur in older patients (median age, 10 years) and are infrequently metastasized at diagnosis. Recent studies have demonstrated the value of methylation profiling in identifying WNT-activated medulloblastomas. These studies included cases that would not be detected using other current testing methods (e.g., beta-catenin immunohistochemistry, CTNNB1 variant analysis, and evaluation for monosomy 6).[117]

Sources: 112 · 116 · 117

CTNNB1 variants are observed in 85% to 90% of WNT medulloblastoma cases, with APC variants detected in many of the cases that lack CTNNB1 variants. Patients with WNT medulloblastoma whose tumors have APC variants often have Turcot syndrome (i.e., germline APC pathogenic variants).[113] In addition to CTNNB1 variants, WNT medulloblastoma tumors show 6q loss (monosomy 6) in 80% to 90% of cases. While monosomy 6 is observed in most medulloblastoma patients younger than 18 years at diagnosis, it appears to be much less common (approximately 25% of cases) in patients older than 18 years.[112,116]

Sources: 113 · 112 · 116

The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region.[118] WNT medulloblastomas are associated with a very good outcome in children, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 variants.[107,119-121] Retrospective studies have suggested that additional TP53 variants and OTX2 copy number gains may be associated with a worse prognosis for patients with WNT medulloblastoma.[122] These latter associations need to be verified in prospective studies.[123]

Sources: 118 · 107 · 119 · 121 · 122 · 123

SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[112] SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and variants in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.[116]

Sources: 112 · 116

Heterozygous deleterious germline pathogenic variants in the GPR161 gene were identified in approximately 3% of cases of SHH medulloblastoma.[124] GPR161 is an inhibitor of SHH signaling. Median age at diagnosis for GPR161-altered cases was 1.5 years. Loss of heterozygosity (LOH) at the GPR161 locus was noted in all tumors, with tumors from five of six patients showing copy-neutral LOH of chromosome 1q (on which GPR161 resides).

Sources: 124

Variants in the third nucleotide (r.3A>G) of the U1 spliceosomal small nuclear RNAs (snRNAs) are highly specific for SHH medulloblastoma.[125,126] U1 snRNA r.3A>G variants are observed in virtually all cases of SHH medulloblastoma in adults, in approximately one-third of cases in children and adolescents, and are absent in cases in infants.[126] U1 snRNA variants disrupt RNA splicing, leading to inactivation of tumor-suppressor genes (e.g., PTCH1) and activation of oncogenes (e.g., GLI2). The significance of U1 snRNA r.3A>G variants in specific SHH medulloblastoma subtypes is described below.

Sources: 125 · 126 · 126

SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:

The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[112] Young children with the MBEN histology have a particularly favorable prognosis.[131-135] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 variants, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[112,127,136]

Sources: 112 · 131 · 135 · 112 · 127 · 136

Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[108,127,136-139]

Sources: 108 · 127 · 136 · 139

The 2021 WHO classification identifies SHH medulloblastoma with a TP53 variant as a distinctive entity (medulloblastoma, SHH-activated and TP53-altered).[1,78] Approximately 25% of SHH-activated medulloblastoma cases have TP53 variants, with a high percentage of these cases also showing a TP53 germline pathogenic variant (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (5-year overall survival rate, <30%).[138] The tumors often show large cell anaplastic histology.[138] A larger retrospective study has confirmed the poor prognosis of these patients.[128]

Sources: 1 · 78 · 138 · 138 · 128

The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly based on the absence of immediate clinical impact for this distinction. Group 3 represents approximately 25% of medulloblastoma cases, while group 4 represents approximately 40% of medulloblastoma cases.[112,116] Both group 3 and group 4 medulloblastoma patients are predominantly male.[101,114] Group 3 and group 4 medulloblastomas can be further subdivided based on characteristics such as gene expression and DNA methylation profiles, but the optimal approach to their subdivision is not established.[112,113]

Sources: 112 · 116 · 101 · 114 · 112 · 113

Various genomic alterations are observed in group 3 and group 4 medulloblastomas. However, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:

Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis.[114] Fewer than 50% of these patients survive 5 years after diagnosis.[112] This poor prognosis is especially true in children younger than 4 years at diagnosis.[108] However, patients with group 3 medulloblastoma without MYC amplification who are older than 3 years have a prognosis similar to that of most patients with non-WNT medulloblastoma, with a 5-year PFS rate higher than 70%.[137,140]

Sources: 114 · 112 · 108 · 137 · 140

Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas. Prognosis may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[105,106,112,136] One study found that group 4 patients with either chromosome 11 loss or gain of chromosome 17 were low risk, regardless of metastases. In cases lacking both of these cytogenetic features, metastasis at presentation differentiated between high and intermediate risk.[136]

Sources: 105 · 106 · 112 · 136 · 136

For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[140] Chromosomal abnormalities include the following:

Sources: SIOP-PNET-4 (NCT01351870) · 140

The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[112,113,139,141,142] Further subdivision within subgroups based on molecular characteristics is likely because each of the subgroups is further molecularly dissected, although the studies are nearing consensus as data from multiple independent studies are merged. As an example, using complementary bioinformatics approaches, concordance was analyzed among multiple large, published cohorts, and a more unified subgrouping was described. For children with group 3 and group 4 medulloblastomas, eight distinct subgroups were determined by DNA methylation clustering. Specific subgroups had different prognoses.[105,116,127,143]

Sources: 112 · 113 · 139 · 141 · 142 · 105 · 116 · 127 · 143

It is unknown whether the classification for adults with medulloblastoma has a predictive ability similar to that for children.[106,108] In one study of adult patients with medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas. However, another study did confirm an excellent prognosis for WNT-activated tumors in adults.[106,108]

Sources: 106 · 108 · 106 · 108

For information about the treatment of childhood medulloblastoma, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.

Sources: Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment

This section describes the genomic characteristics of embryonal tumors other than medulloblastoma and atypical teratoid/rhabdoid tumor. The 2016 WHO classification removed the term primitive neuroectodermal tumors (PNET) from the diagnostic lexicon.[24] This change resulted from the recognition that many tumors previously classified as CNS PNETs have the common finding of amplification of the C19MC region on chromosome 19. These entities included ependymoblastoma, embryonal tumors with abundant neuropil and true rosettes (ETANTR), and some cases of medulloepithelioma. The 2016 WHO classification categorized tumors with C19MC amplification as embryonal tumor with multilayered rosettes (ETMR), C19MC-altered. Tumors previously classified as CNS PNETs are now termed CNS embryonal tumor, not otherwise specified (NOS), with the recognition that tumors in this category will likely be classified by their defining genomic lesions in future editions of the WHO classification.

Sources: 24

The 2021 WHO classification categorizes nonmedulloblastoma embryonal tumors primarily by histological and immunohistological features and, in some cases, by molecular findings. The classification includes the following:[1,78]

Sources: 1 · 78

NEC is defined as a tumor not elsewhere classified. The NOS nomenclature is used for tumors that cannot be further classified. For many lesions, there are overlapping histological features, and methylation-based clustering is critical for specific diagnosis.[1,78]

Sources: 1 · 78

Studies applying unsupervised clustering of DNA methylation patterns for nonmedulloblastoma embryonal tumors found that approximately one-half of these tumors diagnosed as nonmedulloblastoma embryonal tumors showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade gliomas).[28,144] These observations highlight the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.

Sources: 28 · 144

Among the tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:

Although not listed as separate entities in the 2021 WHO Classification of Tumors of the CNS, other nonmedulloblastoma embryonal tumors have also been described as separate entities, including the following:

For information about the treatment of childhood PNETs, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.

Sources: Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment

Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the World Health Organization as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those used for embryonal tumors, the previous convention of including pineoblastoma with the central nervous system embryonal tumors is followed here. Pineoblastoma is associated with germline pathogenic variants in both the RB1 gene and the DICER1 gene, as described below:

Genomic methods have been applied to pineoblastoma in an attempt to learn more about the tumor biology and guide future molecular classification. A retrospective, international meta-analysis included 221 children and adults diagnosed with pineoblastoma (n = 178) and pineal parenchymal tumors of intermediate differentiation (PPTID) (n = 43).[164] The evaluation identified four molecular groups of pineoblastoma based on DNA methylation, transcriptome profiling, and gene sequencing, as described below.

Sources: 164

For information about the treatment of childhood pineoblastoma, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.

Sources: Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment

Molecular characterization studies have previously identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and unique spectrum of genomic alterations (see Figure 6).[166-169]

Sources: 166 · 169

One new molecularly defined ependymoma was added to the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System: spinal ependymoma with MYCN amplification. The 2021 classification further described ependymal tumors defined by anatomical location and histology but not by molecular alteration. These tumors are called posterior fossa ependymoma (PF-EPN), supratentorial ependymoma (ST-EPN), and spinal ependymoma (SP-EPN). These tumors either contain a unique molecular alteration (not elsewhere classified [NEC]) or their molecular analysis failed or was not obtained (not otherwise specified [NOS]).[78]

Sources: 78

Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.

The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:

A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2.[177] Gene expression profiling suggested that these two subtypes may arise in different anatomical locations in the hindbrain. Within both PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.

Sources: 177

The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children. PF-EPN-B is characterized by the following:

ST-EPN-ZFTA is the largest subset of pediatric supratentorial ependymomas and is predominantly characterized by gene fusions involving RELA,[181,182] a transcriptional factor important in NF-κB pathway activity. ST-EPN-ZFTA is characterized by the following:

Sources: 181 · 182

ST-EPN-YAP1 is the second, less common subset of supratentorial ependymomas and has fusions involving YAP1 on chromosome 11. ST-EPN-YAP1 is characterized by the following:

Supratentorial ependymomas without ZFTA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors. As one example, a retrospective methylation analysis of supratentorial brain tumors identified a group of tumors distinct from supratentorial ependymoma that harbor recurrent PLAGL1 fusions.[186] The histological lineage of these PLAGL1-altered tumors is not yet clear. Nineteen of the 32 tumors (59%) had previously been reported as ependymomas. Caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[28,170,187]

Sources: 186 · 28 · 170 · 187

SP-EPN-MYCN is rare, with only 27 cases reported.[188-191]

Sources: 188 · 191

For information about the treatment of childhood ependymoma, see Childhood Ependymoma Treatment.

Sources: Childhood Ependymoma Treatment

Genomic findings related to hepatoblastoma include the following:

Gene expression and epigenetic profiling have been used to identify biological subtypes of hepatoblastoma and to evaluate the prognostic significance of these subtypes.[3,6,7,10]

Sources: 3 · 6 · 7 · 10

Delineating the clinical applications of these genomic, transcriptomic, and epigenomic profiling methods for the risk classification of patients with hepatoblastoma will require independent validation, which is one of the objectives of the Paediatric Hepatic International Tumour Trial (PHITT [NCT03017326]).

Sources: PHITT [NCT03017326]

Genomic findings related to hepatocellular carcinoma include the following:

To date, these genetic variants have not been used to select therapeutic agents for investigation in clinical trials.

Fibrolamellar carcinoma is a rare subtype of hepatocellular carcinoma observed in older children and young adults. It is characterized by an approximately 400 kB deletion on chromosome 19, which produces a chimeric transcript. This chimeric RNA codes for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[14]

Sources: 14

For information about the treatment of childhood liver cancer, see Childhood Liver Cancer Treatment.

Sources: Childhood Liver Cancer Treatment

The genomic landscape of osteosarcoma is distinct from that of other childhood cancers. Compared with many adult cancers, it is characterized by an exceptionally high number of structural variants with a relatively small number of single nucleotide variants.[1,2]

Sources: 1 · 2

Key observations regarding the genomic landscape of osteosarcoma include the following:

Germline variants in several genes are associated with susceptibility to osteosarcoma. Table 5 summarizes the syndromes and associated genes for these conditions. A recent multi-institutional genomic study of more than 1,200 patients with osteosarcoma revealed pathogenic or likely pathogenic germline variants in autosomal dominant cancer-susceptibility genes in 18% of patients. The frequency of these cancer-susceptibility genes was higher in children aged 10 years or younger.[10]

Sources: 10

Variants in TP53 are the most common germline alterations associated with osteosarcoma. Variants in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[11] One study observed a high frequency of young patients (age <30 years) with osteosarcoma carrying a known LFS-associated or likely LFS-associated TP53 variant (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 variant frequency of 9.5%.[12] Other groups have reported lower rates (3%–7%) of TP53 germline variants in patients with osteosarcoma.[10,13,14]

Sources: 11 · 12 · 10 · 13 · 14

Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children’s Research Hospital and 1,127 patients from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function RECQL4 variants, including 5 of 249 patients (2.0%) with osteosarcoma.[15] These RECQL4 variants were significantly overrepresented in children with osteosarcoma, the cancer most frequently observed in patients with Rothmund-Thomson syndrome, compared with 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = .00087; odds ratio, 7.1; 95% confidence interval, 2.9–17). Nine of the 24 individuals (38%) possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis.

Sources: 15

Sources: 16 · 17 · 18 · 18 · 19 · 20 · 21 · 22 · 23 · 24 · 25

For more information about these genetic syndromes, see the following summaries:

For information about the treatment of osteosarcoma, see Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment.

Sources: Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment

The World Health Organization identifies the presence of a gene fusion involving EWSR1 or FUS and a gene in the ETS family as a defining element of Ewing sarcoma.[26] The EWSR1 gene located on chromosome 22 band q12 is a member of the FET family (FUS, EWSR1, TAF15) of RNA-binding proteins.[27] Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of a gene from the ETS family of DNA-binding transcription factors (see Table 6). The FLI1 gene located on chromosome 11 band q24 is a member of the ETS family and is the ETS family fusion partner for EWSR1 in 85% to 90% of pediatric cases of Ewing sarcoma.[28-30] Other ETS family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4, and FEV.[31] Rarely, FUS, another FET family member, can substitute for EWSR1.[32] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. These tumors are thought to be distinct from Ewing sarcoma and are discussed separately. For more information, see the Undifferentiated Small Round Cell (Ewing-Like) Sarcomas section.

Sources: 26 · 27 · 28 · 30 · 31 · 32 · Undifferentiated Small Round Cell (Ewing-Like) Sarcomas

The EWSR1::FLI1 translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[33] two large series have shown that the EWSR1::FLI1 translocation breakpoint site is not an adverse prognostic factor.[34,35]

Sources: 33 · 34 · 35

Besides the consistent aberrations involving the EWSR1 gene, secondary numerical and structural chromosomal aberrations are observed in most cases of Ewing sarcoma. Chromosome gains are more common than chromosome losses, and structural chromosome imbalances are also observed.[36] Two of the more common chromosome aberrations are those involving chromosome 8 or chromosomes 1 and 16.[36]

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The genomic landscape of Ewing sarcoma is characterized by a relatively silent genome, with a paucity of variants in pathways that might be amenable to treatment with novel targeted therapies.[28-30] Recurring genomic alterations are described below. For some of these genomic alterations, claims of prognostic significance have been made. However, these claims need to be viewed cautiously because of the relatively small size of most studies, the low frequency of many of the genomic alterations, the variable use of tumor tissue from diagnosis versus relapse specimens, and the need to consider clinical prognostic factors such as tumor size and the presence of metastatic disease.

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Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A fluorescence in situ hybridization (FISH) rapid analysis looking for a break apart of the EWSR1 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[45] This test result must be considered with caution, however. Ewing sarcomas that harbor FUS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWSR1 FISH break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH (with an EWSR1 break-apart probe) identified eight patients with FUS rearrangements.[46] Four patients who had EWSR1::ERG fusions were not detected by FISH with an EWSR1 break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99. Next-generation sequencing assays, including dedicated fusion panels, are now commonly used in the evaluation of these tumors.

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For information about the treatment of Ewing sarcoma, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.

Sources: Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment