Most low-grade neuroepithelial tumors of childhood are characterized by a singular dominant somatic genetic event that affects protein coding, including genes such as NF1, RAF, or RAS, fibroblast growth factor receptor 1 (FGFR1), and V-Myb avian myeloblastosis viral oncogene homolog (MYB) or in its homolog, MYBL1. Typically such solitary alterations are mutually exclusive.38 Other alterations involve the genes encoding the neurotrophic tyrosine receptor kinase 2 (NTRK2), KRAS, the receptor tyrosine kinase adapter tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), and BRAF.113 Activation of the MAPK/ERK signaling pathway, a primary driver of pediatric low-grade gliomas, is mediated by alterations in BRAF, FGFR1, and NTRK gene family.38,115,116 In a study of 249 pediatric low-grade gliomas that included multiple histologic entities, 90% showed recurrent somatic alterations and 83% showed rearrangements or structural alterations.117
Pediatric-type oligodendrogliomas represent a diagnostic challenge, as they can be histologically indistinguishable from their adult counterparts, yet do not harbor the defining IDH mutations and 1p/19q codeletion. Hence, pediatric oligodendrogliomas are not enriched with a unifying molecular signature. In a study of 50 cases of pediatric oligodendroglioma, only 18% had an IDHR132H mutation and 25% had 1p/19q codeletion with a tendency for those harboring these alterations (“adult-type” oligodendroglioma) to occur in older children and adolescents.120 In addition, nearly half of low-grade pediatric oligodendrogliomas lacked gross somatic cytogenetic alterations.121 As described above, FGFR1 alterations are more frequent in pediatric oligodendrogliomas, but occur in less than half.38,120 BRAF alterations are uncommon, which contrasts to diffuse leptomeningeal glioneuronal tumor (known also as disseminated oligodendroglial-like leptomeningeal tumor), a recently codified entity in the revised fourth edition of the WHO Classification that harbors concurrent KIAA1549:BRAF gene fusions and chromosome 1p deletions.2,8,121,122
The high-grade gliomas arising in childhood comprise a heterogenous group that are molecularly distinct from their adult counterparts, and often harbor specific biological drivers and potentially actionable alterations.116,123–126 In distinction from adults, pediatric high-grade gliomas nearly always arise de novo and only rarely are the result of progression of a lower grade lesion.114 In a study of 127 pediatric high-grade gliomas that included diffuse intrinsic pontine gliomas (DIPG) and non–brainstem gliomas, mutations targeting the RTK/RAS/PI3K pathway, histone modification, or chromatin remodeling and cell cycle regulation were, respectively, found in 68%, 73%, and 59% of cases.123 In this same study 47% had gene fusions, with recurrent NTRK fusions present in 40% of non–brainstem high-grade gliomas in children below 3 years of age.123 Compared with adult GBM’s, TERT-p mutations are much less frequent in childhood (∼3%).95,123
DIPG represents a specific form of pediatric high-grade glioma, typically occurring between 6 to 7 years of age and with a dismal median survival of 10 months.127 H3 K27M mutations are present in over 70% to 80% and PDGFRA amplifications are noted in 28% to 36%.127 Recurrent gain-of-function missense mutations in ACVR1 (also known as ALK2) are present in up to 32% of pediatric DIPGs and can co-occur with H3 K27M mutations.123,128 IDH mutations are not present in DIPGs.127,129 In contrast to the pediatric counterparts, adult brainstem infiltrating gliomas occur less frequently and have a better outcome.129
Korshunov and colleagues recently performed an integrated, large scale genomic and epigenetic analysis of 202 pediatric GBMs which unexpectedly showed that 20% displayed methylation profiles similar to either low-grade gliomas or PXAs, had a better OS and were enriched for PXA-associated molecular alterations including BRAF V600E mutations and homozygous CDKN2A deletions. The remaining 162 pediatric GBMs stratified into the following 4 subgroups: IDH1-mutant (6%), H3.3 G34-mutant (15%), H3.3/H3.1 K27-mutant (43%), and those GBMs that were wt for H3 and IDH (36%).124 Further studies of the heterogenous group of H3-/IDH-wt pediatric GBMs revealed 3 biologically and clinically distinct molecular subtypes with different genomic and epigenetic signatures and these were enriched for MYCN, PDGFRA, or EGFR amplifications.130
Mutations within the N-terminal tail of the histone variants H3.3 (encoded by the H3F3A and H3F3B genes), or H3.1 (encoded by the HIST1H3B and HIST1H3C genes) were first identified within midline pediatric diffuse astrocytomas but more recently have also been recognized in midline tumors of adolescents and adults.69,124,131 Two specific histone mutations in H3.3 are mutually exclusive with IDH mutations; 1 is present at amino acid 27 resulting in a substitution of lysine for methionine (K27M) and the second at position 34 resulting in a substitution of glycine for either arginine or valine (G34R/V).69,132,133 H3 K27M mutations lead to a global reduction of H3K27me3 which in combination with DNA hypomethylation are the major driving forces behind the gene expression pattern conferred by the mutation.134 Reduced H3K27me3 levels can be noted by IHC in those gliomas with H3 K27M mutations.134
The elucidation of the genomic underpinnings of CNS neoplasia has led to the development of an array of biomarkers for robust and reproducible glioma classification. In addition to its diagnostic value, molecular profiling can also identify mutations that involve the germline or are therapeutically actionable.139 The classification of infiltrating gliomas has evolved in parallel with technologically advanced testing and bioinformatics platforms. Many biomarkers have been developed for routine use in diagnostic neuropathology and include IHC, cytogenomic testing platforms, and glioma-tailored NGS, among other molecular-genetic tests.140 Incorporating these test results into integrative diagnoses has markedly improved intraobserver and interobserver variability.9
Depending on the gene and its specific type of alteration, testing can be performed by IHC, FISH, or cytogenomic microarray, focused or high-throughput sequencing technologies, or multiplexed platforms. Gene sequencing is becoming more widely available and can be accomplished with a focused, single gene approach, a targeted gene panel, or whole exome or whole genome approach. Several authors have reported excellent results with customized glioma-tailored NGS panels capable of detecting single nucleotide variations, fusions, and CNAs with substantial concordance when compared with more traditional single biomarker methods.139,141,142 From a diagnostic perspective recurrently altered genes of interest include, but are certainly not limited to, IDH1, IDH2, TP53, ATRX, CIC, FUBP1, PIK3CA, PIK3R1, TERT-p, NOTCH1, DAXX, CDKN2A, EGFR, PTEN, NF1, RB1, BRAF, MET, MYB, MYBL1, MYC, CDK4, CDK6, MDM2, MDM4, KRAS, NRAS, FAT, PTPN11, FGFR1, FGFR3, NTRK, ACVR1, H3F3A, HIST1H3B, PDGFRA, and SETD2. It is fully expected that in the era of precision and personalized medicine NGS will become increasingly available for routine diagnostic neuropathology.113
As the quality and quantity of CNAs across glioma subtypes tend to correlate with classification, grade, progression, and prognosis, MIP array is diagnostically valuable (Fig. 5).4,59,143,144 Of note, FISH is also a widely available and commonly used method that assesses CNAs at a single locus and its clinical utility in diagnostic neuropathology has included detection of EGFR amplifications and deletions of PTEN in high-grade astrocytomas, for example, and 1p/19q codeletions in oligodendrogliomas.13 However, FISH is able to document only focal deletions targeted by specific probes and as whole-arm losses of 1p and 19q have become definitional for oligodendrogliomas it is expected that platforms assessing CNAs across the whole genome will increasingly become more available. As described above, a “false positive” detection rate of ∼6% is expected when using FISH as a marker for 1p and 19q codeletions in the setting of genomic instability in high-grade astrocytomas and this pitfall has been highlighted by several authors.52,145
Amplification events are often prognostically significant and are viewed as potential therapeutic targets in both pediatric and adult glioma.71,124 In IDH-wt GBMs, frequent amplifications include the following ROI: chromosome 7p11.2, 7q21.2, 7q31.2 (EGFR/CDK6/MET genes, respectively); chromosome 12q14.1 and 12q15 (CDK4/MDM2 genes, respectively); and chromosome 4q12 (PDGFRA).99 PDGFRA amplifications are also noted with increased frequency in higher grade IDH-mutant gliomas and appear to represent an independent prognostic factor in de novo IDH-mutant GBMs.149 Another important ROI 7q34 which includes the BRAF gene.
Many of the genetic events that drive gliomagenesis and represent diagnostic biomarkers can be assessed by IHC, a widely available and cost-efficient method with fast turn-around time. IHC for IDH1R132H, p53, ATRX, K27M, and BRAF (VE1) are commonly used for glioma classification; other immunostains including CIC, FUBP1, EGFR, EGFRvIII, and O6-methylguanine-DNA methyltransferase (MGMT) are available but are either used to lesser extents, are not recommended for clinical use or are not available for clinical use.28,87,131 A recent review by Tanboon et al131 addresses the utility of IHC for the diagnosis of gliomas.
A routine panel for the initial diagnostic work-up of diffuse gliomas involves IHC for IDH1R132H, p53, and ATRX. IDH mutations are not only critical for distinguishing between clinically distinct subtypes of gliomas but also to distinguish between glioma and florid reactive gliosis.35 Immunoreactivity for IDH1R132H IHC is strong evidence in favor of a diagnosis of IDH-mutant infiltrating glioma. The R132H variant of IDH1 mutation accounts for >90% of all IDH mutations and a highly sensitive and specific monoclonal antibody that recognizes the mutant protein in the cytoplasm is widely available.32,97 Gene sequencing analysis of IDH1 codon 132 and IDH2 codon 172 is recommended in the event of a negative or indeterminate result with IDH1R132H immunostain given the possibility of a non-R132H IDH mutation (<10% of cases) and the clinical significance of a IDH-wt designation in the context of an infiltrating glioma.13,131 However, it has recently been suggested that IDH sequencing analysis need not follow a negative IDH1R132H immunostain in GBMs arising in patients older than 55 years due to the rarity of variant mutations in older patients.2,3,150,151
In addition to the many genomic alterations that are diagnostically and prognostically relevant, methylation of the promoter for MGMT is one of the most clinically relevant prognostic and predictive biomarkers in adult GBM. MGMT is a DNA repair enzyme capable of restoring guanine from O6-methylguanine induced by alkylating agents commonly used to treat GBM such as temozolomide, thereby hampering its chemotherapeutic effects.95,97 Occurring in ∼40% of GBMs, MGMT promoter methylation correlates with an improved response to therapy and a survival benefit.97 MGMT promoter methylation is commonly assessed by methylation-specific polymerase chain reaction, the only prospectively validated method.13,97,154,155 Others have the utility of pyrosequencing assays.156 MGMT IHC is currently not recommended for clinical practice as MGMT expression has only modest correlation with MGMT promoter methylation status.97,131,157
Ependymomas (EPN) are noninfiltrative gliomas that can arise in patients of any age. Their most common locations are in the posterior fossa (PF), spinal cord, and supratentorial (ST) compartment; they rarely arise outside the CNS. Perivascular pseudorosettes, true rosettes, and ependymal canals represent classic histologic features and well-defined histologic variants include papillary, clear cell, and tanycytic subtypes.2 WHO grade I myxopapillary EPN and subependymomas (SE) are members of the EPN family with specific clinicopathologic presentations and are codified separately.2 Biological behaviors of EPN vary tremendously depending on patient age and location, and the current grading schemes that are intended to stratify risk, especially those for grades II and III, are not optimal.2,158 It is now clear that EPNs are not all created equally, as marked genomic heterogeneity has been recognized across anatomic sites and patient ages, in keeping with known differences in behavior, despite similar histologies.158 The evolving molecular signatures of EPN represent a dramatic improvement in understanding and classification.
Several cytogenetic alterations have been described in EPN: gains of chromosome 1q have been consistently associated with worse outcomes in childhood PF EPN and loss of chromosome 9p (CDKN2A) was equally associated with aggressive behavior in ST tumors, leading to cytogenetic risk-stratification algorithms.159–162 Loss of chromosome 22q (NF2) characterizes the majority of spinal cord EPN, which is not surprising as NF2 mutations are also known to occur in this subset.162 Chromosome 22 loss without NF2 mutations have also been noted in group B PF EPN.163 PF EPN exhibit low mutation rates and gene amplification events are almost totally absent.162,164 Overall, genomic alterations including single nucleotide variations, insertions/deletions and focal CNAs are rare in EPN; however, structural variations are enriched in ST EPN.165
The molecular subgrouping of EPN across anatomic compartments has been shown to be superior to histologic grading in terms of risk-stratification. Nine molecular subgroups of EPN have been recognized by genome-wide methylation and gene expression profiling, each with varying clinical and histopathologic features.162 Three discrete groups were identified in each of the anatomic compartments as follows: (I) the ST compartment includes EPN with either RELA or YAP1 fusions, as well as a third group of SE that involve the lateral ventricles (in short, ST-EPN-RELA, ST-EPN-YAP1, ST-SE, respectively); (II) the PF included group A and B EPNs as well as SE that involves the fourth ventricle (in short, PF-EPN-A, PF-EPN-B, and PF-SE, respectively); (III) the spinal (SP) compartment included classic EPN in addition to myxopapillary ependymoma (MPE) arising in the region of the cauda equina and SE (in short, SP-EPN, SP-MPE, and SP-SE, respectively).162 Numerous important clinicopathologic associations were readily apparent as nearly all cases of PF-EPN-A occurred in children aged below 8-years old (median age, 3 y), whereas the vast majority of PF-EPN-B cases arose in older children and young adults.162,163 Approximately 75% of the RELA-fused EPN occurred in children with a median age of 8 years and the remaining quarter arose in adults. MPE and SE across all compartments occurred only in adults.162
Loss of chromosome 6 is frequently observed in SE (SP-SE and PF-SE) and PF-EPN-B tumors.162 Tumors in the PF-EPN-B class exhibit a high degree of genomic instability with frequent whole chromosomal or whole chromosomal arm gains and losses, whereas PF-EPN-A exhibit largely balanced genomes albeit with a propensity for chromosome 1q gain, a known independent factor of poor prognosis.162,163 The oncogenic driver of the ST-EPN-RELA tumors is the C11orf95-RELA-fusion and these are also enriched for homozygous CDKN2A deletions. YAP1-MAMLD1 and YAP1-FAM118B fusions were identified in the ST-EPN-YAP1 class of EPN and they also had focal CNAs of chromosome 11 around the YAP1 locus rather than the chromothripsis event characteristic of ST-EPN-RELA tumors.162 Poor clinical outcomes have been observed for ST-EPN-RELA and PF-EPN-A classes, which together represent up to two thirds of all EPN, with 10-year PFS and OS ∼50% and 20%, respectively.162 Witt et al163 similarly reported contrasting outcomes for PF EPN subgroups, with 5-year of PFS and OS of 47% and 69%, for group A tumors and 79% and 95% for group B tumors, respectively.
As distinct methylomes are observed in PF-EPN-A and PF-EPN-B tumors, others have attempted to correlate this finding with specific methylation markers. Using mass spectrometry-based technology, 1 group identified 3 genes with CpG hypermethylation in PF-EPN-A but not in PF-EPN-B, demonstrated distinct H3K27me3 signatures that could robustly stratify them and concluded that PF-EPN-A have a CIMP phenotype.164 Additional studies indicated that H3K27me3 immunostaining was significantly reduced in PF-EPN-A compared with PF-EPN-B tumors and suggested its use as an independent biomarker of poor prognosis.167,168 DNA methylation analysis also demonstrated that PF-EPN-A exhibited similarities to H3 K27M-mutant gliomas.167 Interestingly, 2 childhood PF-EPN-A harboring H3 K27M mutations (confirmed by NGS) that showed strong nuclear H3 K27M IHC and reduced nuclear labeling with H3K27me3 IHC where recently reported.169 Other markers are being pursued for more reliable risk-stratification.170–172
Loss of chromosome 17p is present in 25% of SHH-activated medulloblastomas and is associated with unfavorable outcomes. Gain of chromosome 3q, loss of 10q, and GLI2 amplifications have also been associated with poor outcomes in this subset, albeit with some contradicting results.184,185 Focal deletions of PTEN occur exclusively in pediatric SHH-activated medulloblastomas, contributing to PI3K pathway deregulation.182,183 PI3K/AKT pathway activation in adult SHH-activated medulloblastoma has also been associated with poor outcomes.189
The non-WNT/non-SHH medulloblastomas comprise 60% of all medulloblastomas. Group 3 tumors (∼20% of all cases) are characterized by MYC amplifications, whereas chromosome 17 alterations (predominantly an isochromosome 17) are found in ∼80% of group 4 medulloblastomas (∼40% of all cases).179 Within group 3 medulloblastomas PVT1-MYC fusions have been described in at least 60% of MYC-amplified cases and are thought to arise from chromothripsis of chromosome 8q.182,183 Among group 3 medulloblastomas, chromosome 1q gain, 17p loss, 17q gain, isochromosome 17q, and MYC amplification are associated with worse outcomes.185 Among group 4 medulloblastomas, most females exhibit loss of 1 copy of the X chromosome.182 MYCN and CDK6 amplifications also occur in group 4 medulloblastomas.184 Gains of chromosome 17 and loss of chromosome 11 have been associated with better outcomes in group 4 medulloblastomas.185
As the historic term “CNS primitive neuroectodermal tumor (PNET)” has become discouraged, these undifferentiated and “primitive-appearing” neoplasms are now referred to as embryonal tumors by the WHO and are considered grade IV.2 Following extensive molecular analysis that included genome-wide DNA methylation and copy number profiling, a single diagnostic category emerged that included the following 3 previously codified malignancies: embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma.194 These tumors are now collectively referred to as ETMRs, which are unified by the morphologic finding of embryonal tumor cells forming multilayered rosettes and by the highly specific focal amplification and fusion of chromosome 19q13.42 (Fig. 16). This region encodes the largest human microRNA cluster, C19MC, and the alteration is not present in other pediatric tumors. With this new definition, ETMR is regarded as a universally aggressive embryonal tumor with median OS around 12 months.194–199 These tumors can arise anywhere within the ST or, to a lesser extent, the infratentorial compartments and preferentially affect a very young patient population with the vast majority of cases occurring before 4 years of age.194,199 As the name implies, well-defined multilayered and/or pseudostratified rosettes (ependymoblastic and medulloepithelial rosettes) are key histologic features of the entity along with variable proportions of small undifferentiated blue cells and neuropil that contribute to its heterogenous histomorphologic spectrum.2,194
Upregulation and overexpression of LIN28A, an RNA-binding protein, is highly correlated with the C19MC alteration. Although not entirely specific, strong LIN28A cytoplasmic immunoreactivity is a fairly sensitive marker of ETMRs, with the important caveat that a smaller proportion of high-grade gliomas and AT/RTs can be positive, albeit not as strongly and diffusely in the majority of cases.194,199–201 Thus, LIN28A immunoreactivity alone may be insufficient to establish a diagnosis of ETMR and other embryonal neoplasms such as AT/RT need to be ruled out. The hallmark focal high-level amplification at 19q13.42, identified by FISH or cytogenomic microarray, is the most robust diagnostic test for this entity (Fig. 16).194 Complex rearrangements within the same locus as well as fusion of C19MC to the promoter of the brain-specific TTYH1 gene (TTHYH1:C19MC) can also contribute to tumorigenesis by mediating high expression of the oncogenic microRNA cluster.194,197
The hallmark alteration of AT/RTs, a WHO grade IV embryonal tumor, is deletions or loss-of-function mutations of SMARCB1 (BAF47/INI1/hSNF5) at chromosome 22q11.2 or to a much lesser extent SMARCA4 (BRG1) at chromosome 19p13.2.202–205 AT/RTs account for 1% to 2% of all pediatric CNS tumors and typically arises in the ST or infratentorial compartments of young children (< 3 years) with a third of the cases arising within the first year of life.206 The worst outcomes are observed in patients below 6 months of age. However, a recent Canadian AT/RT registry study of patients in their first year of life suggested that high-dose chemotherapy was associated with better OS when compared with conventional chemotherapy approaches (5-year OS of 52.0%±8.3% vs. 10.7±4.5%, respectively).206 A study of AT/RT patients that included a wider age range (0 to 18 y) reported a median OS of 14.3 months and a 5-year OS rate of 29.9%.207 As a standard therapy is yet to be defined and the risk-benefit of radiotherapy is further refined, variation in treatment modalities for AT/RT patients likely account for the wide range of clinical outcomes that are reported, although it should be noted that outcomes have improved in recent years.208,209 Screening for germline mutations in AT/RT should be considered when making the diagnosis, particularly in the very young, as roughly one third of cases arise in the setting of Rhabdoid Tumor Predisposition Syndrome.206,209
AT/RTs are known to be mimickers of other neoplastic disease and they exhibit marked histomorphologic heterogeneity due to their differentiation along distinct phenotypic lines (teratoid), a finding highlighted by an indiscriminate immunoprofile.203,204 A small blue cell population can be prominent within AT/RTs, requiring caution to avoid an erroneous diagnosis of medulloblastoma when the tumor arises in the PF; the above discussed biomarkers in conjunction with INI1 IHC are diagnostically helpful.203 Differentiation of AT/RT from choroid plexus carcinoma poses an equally difficult diagnostic dilemma on histomorphologic assessment do to their overlapping features; however, INI1 and Kir7.1 IHC are of great utility in this differential diagnosis.210–212 Tumor cells with eccentric nuclei, vesicular chromatin, and prominent nucleoli in conjunction with eosinophilic cytoplasm and globular inclusions (rhabdoid cells) are, however, typical of AT/RT and an important diagnostic clue (Fig. 17).
Recent transcription, methylation, and copy number profiling have identified molecular subgroups of AT/RTs characterized by activation of distinct signaling pathways, a finding that may explain the clinical heterogeneity of these aggressive tumors.215,220,221 One subset showed upregulation of Notch signaling pathway genes, with consistently increased expression of ASCL1, a Notch regulator. This group tended to arise supratentorially and had improved 5-year OS when compared with ASCL1-negative tumors.220 The prognostic significance of ASCL1 (assessed with IHC) was independent of treatment protocols.220 In contrast, upregulation of genes involved in the bone morphogenetic protein signaling pathway have been associated with infratentorial tumors and worse outcomes.220 More recently, 3 epigenetically defined subgroups of AT/RTs with differences in patient ages, tumor location, and type and extent of SMARCB1 alterations were described: (I) ATRT-TYR (overexpression of melanosomal markers including the enzyme tyrosinase), (II) ATRT-SHH (overexpression of genes in the SHH pathway, such as MYCN and GLI2, as well as genes in the Notch pathway, including ASCL1), and (III) ATRT-MYC (overexpression of the MYC oncogene and HOX cluster genes).215 These 3 epigenetically defined subsets of AT/RT, each with distinct clinical characteristics, were subsequently corroborated and subgroup-specific therapeutic sensitivities were demonstrated.221 The emerging subclassificaton of AT/RTs, together with clinical risk factors, may allow for targeted therapies as well as therapeutic stratification.209
Embryonal tumors other than those described above can also rarely present as primary CNS neoplams, most often in childhood. They too exhibit small poorly differentiated cells (small blue cell tumors) and share similar biological behaviors including an increased propensity for metastatic leptomeningeal dissemination. The revised fourth edition of the WHO recognizes that tumors corresponding to this category include medulloepitheliomas lacking C19MC amplification, CNS neuroblastomas, and CNS ganglioneuroblastomas.2 After careful consideration of alternate entities, a diagnosis of “CNS embryonal tumor, NOS” may be warranted in the appropriate clinicopathologic context. Before rendering any of these diagnoses, molecular-genetic and biomarker testing should be performed to rule out other tumors, such as medulloblastoma, C19MC-altered ETMR, AT/RT, and high-grade glioma. In this setting IHC for GAB1, YAP1, LIN28A, L1CAM, INI1, IDHR132H, H3K27M, and BRAF V600E can offer a practical approach and be of diagnostic utility.
Advances in molecular profiling of primary CNS tumors have not been confined to the entities described above and significant findings have been reported for meningiomas, primary CNS melanocytic neoplasms, peripheral nerve sheath tumors, hematopoietic neoplasms, tumors of the sellar region, and other mesenchymal neoplasms (recently reviewed by Sahm et al225). Many of these remarkable changes are already reflected in the most recent edition of the WHO classification and are routinely used for diagnostic purposes. For example, the presence of NAB2-STAT6 fusions in most solitary fibrous tumors/hemangiopericytomas allows for the use of STAT6 IHC for definitive diagnosis. Similarly, GNAQ and GNA11 mutations confirm a diagnosis of primary CNS melanocytic neoplasms and exclude other diagnostic possibilities such as melanotic schwannoma (malignant melanotic schwannian tumor) or metastatic melanoma. Other uncommon neoplasms that arise within the CNS harbor mutations that may be targetable. For example, many cases of Erdheim-Chester disease will have a BRAF V600E mutations and inflammatory myofibroblastic tumor may have ALK and RET rearrangements, or much less commonly a TFG-ROS1 fusion as we recently showed (published in abstract form).226 In such cases, neuropathologists play a key role in uncovering genetic signatures of prognostic and predictive value.
Neuropathologists, molecular pathologists, and clinicians now work closely together to provide optimal clinical care by utilizing molecular biomarkers for diagnostic and treatment purposes.227–230 Without doubt, the expanded molecular profiling of CNS tumors has improved our diagnostic algorithms, risk-stratification schemas and has opened the door to the development of targeted therapies.
The authors are appreciative of Jennifer E. Hauenstein, MS, from the Emory Oncology Cytogenetics laboratory who kindly provided all the MIP array illustrations. The authors also acknowledge Brent A. Orr, MD, PhD (St. Jude Children’s Research Hospital) for his collaboration and the courtesy of providing the FISH images shown in Figures 13 and 16. The authors thank Arie Perry, MD, and David Solomon, MD, PhD (University of California, San Francisco) for performing and analyzing the NGS molecular studies that led to the integrative diagnosis of the CNS HGNET-BCOR case illustrated in Figure 18. The authors equally thank Matthew J. Schniederjan, MD, for providing exemplary cases of childhood CNS neoplasia and Stewart G. Neill, MD, Debra F. Saxe, PhD, and Michael R. Rossi, PhD, for their expertise in the interpretation of MIP arrays that were submitted by the Emory Neuropathology Division.
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