| Abstract|| |
Low-grade gliomas are the most common primary central nervous system (CNS) neoplasms in the pediatric age group. The majority of these tumors are circumscribed, while diffuse low-grade gliomas are relatively rare. The pediatric type diffuse low-grade gliomas (pDLGG) have a distinctly different biological behavior, molecular profile, and clinical outcome as compared to their adult counterpart. In the 5th edition of World Health Organization (WHO) CNS classification, pDLGGs are subclassified into four distinct histomolecular entities, namely, (i) diffuse astrocytoma, MYB- or MYBL1-altered, (ii) angiocentric glioma, (iii) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (iv) diffuse low-grade glioma, MAPK pathway-altered. Although the molecular profile, to a great extent, aligns with the morphological features, it is not specific. Many of the molecular alterations described in pDLGG have therapeutic implications with the availability of newer targeted therapies. A wide range of testing platforms are available for routine assessment of these molecular alterations in clinical laboratories, though WHO does not recommend any particular method.
Keywords: Glioma, low grade, pediatric
|How to cite this article:|
Purkait S, Mahajan S, Sharma MC, Sarkar C, Suri V. Pediatric-type diffuse low grade gliomas: Histomolecular profile and practical approach to their integrated diagnosis according to the WHO CNS5 classification. Indian J Pathol Microbiol 2022;65, Suppl S1:42-9
|How to cite this URL:|
Purkait S, Mahajan S, Sharma MC, Sarkar C, Suri V. Pediatric-type diffuse low grade gliomas: Histomolecular profile and practical approach to their integrated diagnosis according to the WHO CNS5 classification. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 24];65, Suppl S1:42-9. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/42/345032
| Introduction|| |
Central nervous system (CNS) tumors are the most frequent solid neoplasm of childhood of which 45.7% are gliomas., While the World Health Organization (WHO) classification of adult diffuse gliomas was significantly updated in the 2016 revision based on the isocitrate dehydrogenase (IDH), alpha thalassaemia mental retardation, X-linked (ATRX) gene mutation and 1p/19q co-deletion, the classification of pediatric diffuse gliomas was not revised due to a lack of adequate data. The 2016 WHO CNS instead only gave these tumors provisional nomenclature, such as “pediatric diffuse astrocytoma” and “pediatric-type oligodendroglioma.” Though pediatric and adult gliomas share similar histological features, pediatric gliomas differ substantially from their adult counterparts in terms of primary molecular alterations and biological behavior. Thus, in the 5th edition of WHO CNS classification (WHO CNS 5), pediatric gliomas are entitled as an independent group for the first time and are further subclassified into pediatric type low and high-grade diffuse gliomas. Pediatric low-grade gliomas (pLGG) encompass a heterogeneous group of tumors and constitutes approximately one-third of the childhood CNS tumors. On histomorphology, they can be circumscribed or diffusely infiltrating., Although these tumors usually have a favorable prognosis, pediatric type diffuse low-grade gliomas (pDLGGs) display variable clinical behavior owing to their diffusely infiltrating nature.,,, Over the last few decades, genome-wide molecular-profiling studies have elucidated characteristic genetic and epigenetic alterations associated with different types of gliomas, which can be used as diagnostic, prognostic, and predictive biomarkers and for some entities, suggest targeted therapies. Using these recent insights The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) has made pragmatic suggestions to the WHO CNS 5 tumor classification of combining histologic and molecular parameters for the integrated diagnosis of brain tumors.
In WHO CNS 5 classification, pDLGGs are subclassified into four distinct histomolecular entities [Table 1]. The diagnosis of these tumor entities critically depends upon the histomorphological and molecular features. Incorporating all this information in a layered diagnosis system was first suggested by the 2014 International Society of Neuropathology-Haarlem consensus and then incorporated in the WHO CNS 2016 classification. There is a substantial degree of overlap in the histological features as well as molecular markers between pDLGG and low-grade circumscribed gliomas. Further, adult-type diffuse low-grade gliomas can also rarely occur in the pediatric age group. Thus, overalapping features can lead to diagnostic difficulty, especially in smaller tissue specimen. Hence, a significant portion of the diagnostic algorithm involves exclusion of other morphological and molecular mimics.
|Table 1: WHO CNS 5 classification of pediatric-type diffuse low-grade gliomas|
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| Molecular Profile OF pDLGG|| |
The molecular alterations commonly encountered in this group of tumors include MYB or MYBL1 structural variations, BRAFV600E mutation, and FGFR1 alterations.,, To a greater extent, these genetic alterations are aligned with the clinical setting and pathological features of the tumors and are the only potential genetic driver in the majority of the cases. Further, these alterations are mostly mutually exclusive. Some of these genetic alterations like BRAF and FGFR alterations can be seen in a small fraction of high-grade gliomas as well. Hence, the molecular alterations should always be interpreted in the context of morphology. According to the definition by WHO, morphological atypia and mitotic activity should be absent or at low level, and endothelial proliferation or necrosis should be absent in pDLGGs. Cases with probable morphology of pDLG but with any of the above features should be subjected to evaluation for molecular alterations like IDH mutation, 1p/19q co-deletion, histone H3 gene mutations, and CDKN2A/B deletion.,,
MYB or MYBL1 alterations
MYB is a proto-oncogene located in the long arm of chromosome 6 and codes for transcription factors responsible for cellular proliferation and differentiation. MYBL1 (MYB Proto-Oncogene Like 1, located in the long arm of Chromosome 8) is closely associated with MYB and has a similar function. Alterations of these genes have been implicated in various hematological and solid malignancies., The pDLGG cases with alterations in MYB or MYBL1 gene have been reported to be clustered as a single tumor on the methylome-based study and hence considered as one entity. MYB or MYBL1 altered tumor is common in younger children (median-approximately five years), with the cerebral hemisphere being far more common site than the midline/brain stem. The common structural variations described in cases of pDLGG include MYB or MYBL1 rearrangements and MYB-QKI fusion, which are associated with increased expression of these genes. The other less common alterations include MYB-ESR1 fusion, MYB-MAML2 fusion, etc. The MYB/MYBL1 alterations are associated with diffuse astrocytoma (DA) histology and documented in 22%–41% of cases.,,,, The tumors with MYB or MYBL1 alterations have a good prognosis despite the diffusely infiltrating morphology with a 10-year overall survival (OS) of almost 90%. MYB-QKI fusion is regarded as a specific marker for angiocentric gliomas (AG) and is characteristically seen in almost 87% of cases.,,,,
Fluorescence in situ hybridization (FISH) assay is routinely implemented for the detection of MYB and MYBL1 alterations, which uses a combination of three probes targeting the 5' region and 3' region of the respective gene and centromeric probe chromosome 6 and 8 (CEP 6 and 8 respectively) was used., This procedure is relatively labor-intensive, costly, requires expertise for analysis, and can detect only one alteration at a time. However, it is one of the useful first-line assays. Transcriptional targets of MYB-QKI-like KIT and/or CDK6 can be approached for targeted therapy., The tumors with MYB alterations have been found to be associated with increased expression of MYB at the protein level by immunohistochemistry (IHC). However, the role of IHC in detecting MYB alterations requires further validation.
The two common alterations of BRAF gene in the context of pLGG are BRAFV600E mutation and KIAA1549-BRAF fusion. BRAFV600E mutation is a missense mutation characterized by the substitution of valine with glutamic acid at the 600th position associated with constitutive activation of the protein product. On the other hand, the fusion is associated with loss of regulatory domain of BRAF and downstream up-regulation of the RAS/MAPK pathway.,, Among the pLGG, BRAFV600E mutation has been documented in both diffuse gliomas and circumscribed glial/glioneuronal tumors. However, KIAA1549-BRAF fusion is commonly seen in circumscribed gliomas (especially pilocytic astrocytoma (PA)) and is extremely rare in pDLGG. BRAFV600E mutation does not have any specific association with the histomorphological features and has been reported in approximately 23%–43.5% of cases of pediatric diffuse astrocytoma in different series. The occurrence of this genetic alteration in tumors with oligodendroglial morphology is relatively rare (0%–8%).,, Its occurrence has also been reported in tumors with morphological features of PLNTY (approximately 43%). As a group, pLGGs with BRAF V600E have worse OS and progression-free survival (PFS) compared to other pLGG and they are also associated with a higher risk of transformation to high-grade glioma and poor response to chemoradiation. The other forms of BRAF alteration, including inframe insertion, single nucleotide variation (SNV) other than V600E, translocations are extremely rare in pDLGG.
The BRAF V600E mutation can be efficiently detected by IHC by using clone VE1 (catalog no. 790-4855; 1/100 titer) on the Ventana BenchMark Ultra platform (Ventana Medical Systems, Inc., Tucson, AZ, USA) with more than 90% sensitivity and specificity. The other commonly used method for detection is Sanger sequencing. Considering the cost-effectivity, ease of analysis, and feasibility in formalin-fixed paraffin-embedded tissue samples, it is often regarded as the gold standard., The KIAA1549-BRAF fusion can be detected effectively by FISH.,
Apart from its diagnostic implications, BRAF V600E is one of the important therapeutic targets. The kinase inhibitor, PLX4032 (vemurafenib) is approved by FDA for the targeted therapy of metastatic melanomas. BRAF inhibitors have also shown promising therapeutic potentials in a large cohort of pLGG with BRAF V600E mutation.
FGFR1 is one of the receptor tyrosine kinases (RTK) expressed on the cell membrane and plays a crucial role in cellular development. The intracellular domain of the receptor has tyrosine kinase activity (TKD) and is responsible for signal transduction. Dysregulation of FGFRs has been documented in a wide range of solid malignancies. FGFR-1 alterations in pLGG are activating type and attributable to three main mechanisms, including FGFR1 mutations, FGFR1-TACC1 fusions, and FGFR1-TKD duplications. All these alterations ultimately lead to the activation of the RAS/MAPK pathway.,, The mutations and duplications are frequently seen in glioneuronal tumors, especially dysembryoplastic neuroepithelial tumor (DNET). Among the diffuse gliomas, FGFR1 alterations are relatively more common in tumors with oligodendroglial morphology. FGFR1-TKD duplication and FGFR1-SNV/missense mutation have been reported in approximately 10%–20% of the pediatric oligodendrogliomas (ODG), while FGFR1-TACC1 fusion in 3%–5% cases. FGFR-1 SNV is rare (< 5%) in DAs. Although this alteration is associated with poor prognosis in patients of PA, its clinical implication in pDLGG is yet to be established.,,
The FGFR1 fusion-related alterations can be detected by FISH, while SNV can be detected by Sanger sequencing. However, assessment of TKD is done in most of the studies using NGS-based platform.,
This molecular alteration is another druggable target. Several FGFR inhibitors are being used in various clinical trials for treating CNS malignancies (NCT01975701, NCT028224133, NCT02052778, NCT01948297). One of these studies documented effective growth inhibition of pediatric diffuse midline glioma by FGFR inhibitors (AZ4547, dovatinib, PD173074, ponatinib).,
Other genetic alterations
Various other genetic alterations related to MAPK pathway have also been described but with a very low frequency and hence not discussed. One of the recently described genetic alterations that appear to be of importance is FGFR 2/3 fusion. This genetic alteration has been detected in up to 50% of cases of PLNTY.,
| Histological Features|| |
A substantial proportion of pDLGGs have morphological features similar to adult astrocytoma, ODG, or mixed tumor on histology. These tumors are further classified based on their genetic backgrounds. On IHC, the tumor cells are typically positive for GFAP and Olig2, indicating glial differentiation. The neuronal markers including synaptophysin, chromogranin, and Neu N are negative. The MIB-1 labeling index (MIB1-LI) is very low. Some of these tumors (AG, PLNTY) show few specific histological and immunohistochemical features.,,
Angiocentric glioma was first described in 2005 by Wang et al. as an infiltrative low-grade epileptogenic cerebral glioma. It was recognized as a distinct entity in the WHO 2007 classification and was enlisted under the subgroup of “other neuroepithelial tumors”. It was defined as “an epilepsy-associated, stable, or slowly growing cerebral tumor primarily affecting children and young adults; histopathologically characterized by an angiocentric pattern of growth, monomorphous bipolar cells, and features of ependymal differentiation.” The definition remained same in WHO 2016 classification, though it got enlisted under the subgroup “Other Gliomas.” Later in 2017, studies documented AGs arising in the brainstem as well. It constitues less than 1% of all pLGGs. The median age at presentation is approximately 13 years with a wide age range (1.5–80 years). The majority of the tumors are hemispheric with the temporal and frontal lobes being the common locations. AG usually presents as drug-resistant intractable epilepsy and is enlisted under long-term epilepsy-associated tumors (LEATs)., The tumor usually have a favorable prognosis and correspond to WHO grade 1.
Macroscopically they are usually circumscribed solid cystic tumors causing expansion of the involved structures leading to blurred gray/white matter junction. On histology, monomorphic bipolar cells with a spindled nucleus and granular chromatin arranged around the cortical blood vessels is characteristic of this tumor [Figure 1]. The perivascular orientation can sometimes mimic an ependymal pseudorosette or an astroblastic rosette. Areas with compact growth pattern with foci of nested epithelioid cells have also been documented. Frequent sub-pial palisaded arrangement of the tumor cells has also been described. The features of higher histological grade, including mitosis, necrosis, and endothelial proliferation, are generally absent.
|Figure 1: Morphological features of angiocentric glioma. Histopathological examination reveals a tumor composed of infiltrative cytologically bland bipolar cells (a) forming perivascular pseudorosettes at places (b). Immunohistochemical staining demonstrates diffuse and strong cytoplasmic immunoreactivity for GFAP (c) and dot-like immunostaining for EMA (d)|
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Apart from positivity for GFAP, the tumor cells show perinuclear dot-like or ring-like positivity for EMA similar to ependymoma (EPN).,, Predominantly, they are OLIG2 negative. MIB-1 LI is mostly less than 5%. It was not until late 2016 that MYB-QKI fusion was reported to be a specific driver event in AGs and was seen in 87%–100% of cases. The remaining generally harbored other MYB alterations.,,,, AGs do not harbor mutations in IDH, ATRX, TP53, and Histone 3 genes.
Differential diagnosis of AGs includes EPN and pilomyxoid astrocytoma (PMA). However, AG differs from EPN by its origin in cortex, prominent bipolar spindle cell morphology, and diffuse and infiltrative growth pattern not classically seen in EPN. PMA may resemble AGs with a vasculogenic arrangement of bipolar spindle cells but they are characterized by non-infiltrative growth and prominent mucinous background not encountered in AGs.,,
Polymorphous low-grade neuroepithelial tumor of the young
Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a newly described tumor entity with a relatively rare occurrence. To the best of our knowledge, less than 20 cases have been reported in the literature. The median age of presentation is approximately 16 years (range: 4–57 years). It is an epileptogenic tumor, enlisted under LEATs and corresponds to WHO grade 1. Surgical resection is curative in most cases. They mostly arise in the cerebral hemispheres with predilection for the right temporal lobe (80%). They usually have both cortical and subcortical components. Macroscopically they are generally solid-cystic unencapsulated tumors indistinctly delineated from the surrounding normal brain presenting as soft friable gray-white lesion., Histologically, PLNTY predominantly comprises oligodendroglia-like cells exhibiting compact growth pattern with infiltrating margins [Figure 2]. They may also display vague perivascular pseudorosetting and fibrillary, spindled or pleomorphic astrocytic cells. Calcification is common and may be coarse and confluent. Rosenthal fibers, gemistocytes, high mitotic activity, necrosis, endothelial proliferation, neuronal differentiation and other features indicative of high-grade malignancy are usually absent. Eosinophilic granular bodies can be infrequently noted. The adjacent cortex may show evidence of focal cortical dysplasia.,, In the past, tumors with similar histomorphology and clinical picture have been reported as unusual variants of DNET, diffuse glioneuronal tumors, extensively calcified low-grade glioma, and pediatric-type ODGs.
|Figure 2: Morphological features of PLNTY. Histopathological examination reveals a tumor composed of oligodendrocyte like cells with round and oval nuclei, perinuclear clearing, and delicate vascular network. Mitoses, microvascular proliferation, and necrosis are absent (H & E) (a). Focal cortical dysplasia noted adjacent to the tumor characterized by cortical architectural disorganization (H & E) (b). GFAP immunostain is diffusely expressed (c) and the tumor cells are diffusely and strongly immunopositive for CD34 (d)|
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Immunohistochemically, glial differentiation is evident. Strong immunopositivity for GFAP and OLIG2 is commonly seen. Expression of CD34 may be strong and diffuse or may be focal. They are typically immunonegative for IDH1 R132H, EMA, NeuN, and neuroendocrine markers. MIB-1 labelling index is generally low (<1%–2%). Molecular analysis of this entity reveals either BRAF V600E mutation (≈40%) or FGFR 2/3 fusion (≈50%).,
PLNTYs are histologically indistinguishable from ODGs or DAs. However, PLNTYs show intense positivity for CD34 and commonly display MAPK pathway alterations, which are usually not seen in oligodendroglial tumors and other glioneuronal tumor with oligo-like components. Furthermore, PLNTYs do not exhibit IDH mutations or 1p/19q co-deletion frequently encountered in the latter tumors.,,
Diffuse gliomas without any specific histological feature
Diffuse astrocytoma, MYB or MYB1 altered
It constitutes approximately 2% of all pLGG and forms the major bulk of the pDLGGs. Pediatric type DA is just a morphological entity and the final diagnosis depends upon the associated molecular alteration. The median age at presentation is approximately 10 years with a wide age range (1–35 years). They are mainly localized in cerebral hemispheres and commonly comprise cortical and subcortical components. Rarely, DA arising in brainstem have also been reported. They are also enlisted under the category of LEAT. Grossly these tumors usually present as unencapsulated, soft friable masses. They are morphologically indistinguishable from their adult-type counterpart and are considered as WHO grade 1 tumor. Apart from the diffusely infiltrating growth pattern, they have relatively low cellularity and are composed of monomorphic tumor cells with minimal nuclear atypia in a fibrillary matrix. They are usually devoid of mitotic activity with the absence of necrosis or endothelial proliferation. Focal angiocentric rossettes may be present.,, There is no specific immunohistochemical feature though they are GFAP positive, OLIG2 and CD34 negative. MIB-1 labelling index is typically low. The molecular profile of these tumors is distinctly different from their adult counterpart as they do not harbor IDH, TP53, ATRX or histone 3 mutations. The molecular alterations, which are commonly associated with this group, are fusion between MYB or MYBL1 and a partner gene. The most commonly documented fusion partner is PCDHGA1, MMP16, and MAML2. MYB-QKI fusion is rare in this group.,,
Histologically these tumors show some morphological overlap with AGs and they both harbor MYB or MYBL1 alteration; however, AGs are typically associated with MYB-QKI fusion in ≈ 90% cases. They are also morphologically indistinguishable from their “adult-type” IDH mutant or IDH wild-type DAs though they harbor different molecular alterations.
The prognostic outcome of this group is excellent with studies suggesting a relatively benign clinical behavior (10-year PFS and OS rates of 89.6% and 95.2%, respectively)., More than 90% of the patients have been reported to be epilepsy free after they undergo resection.
Diffuse low-grade glioma, MAPK pathway-altered
These are also rarely encountered in the pediatric age group and constitute approximately 9% of all pLGG. They can have either diffuse astrocytic or oligodendroglial morphology and harbor MAPK pathway alterations. Molecular alteration commonly encountered is BRAF V600E mutation and FGFR1 alteration, which in turn can be either TKD duplication, single nucleotide variation or a fusion. Rare alterations documented in these tumors include mutations in FGFR2, NTRK1-3, MAP2K1, and MET genes.,, They can occur throughout the craniospoinal axis but predominantly in the cerebral hemispheres. Seizure is a common presenting clinical feature. These tumors have a diffusely infiltrating growth pattern and consist of bland appearing mildly pleomorphic glial cells with entrapped normal brain. Further morphological features are frequently associated with the specific MAPK pathway alteration.
pDLGG, FGFR1 altered
These tumors usually have morphological features of an ODG, though astrocytic morphology has also been described. Calcification can be seen. Features of high-grade glioma are absent. Immunohistochemically they show diffuse positivity for OLIG2 and variable positivity for GFAP. CD34 expression is encountered in only few cells.,,
Differential diagnosis includes DNET, PLNTY, and “adult-type” IDH mutant ODG. DNET frequently show glioneuronal component and sometimes glial nodules. PLNTYs can be distinguished by diffuse and strong CD34 expression and adult type ODG by the presence of IDH mutation.
pDLGG, BRAF V600E mutant
These tumors usually have an astrocytic morphology comprising of minimally pleomorphic glial cells with bland nuclei in a fibrillary matrix. Rosenthal fibers and eosinophilic granular bodies are usually not encountered. Mitotic activity is rare or low. Necrosis and microvascular proliferation are absent. These tumors are diffusely immunopositive for GFAP and OLIG2. This diagnosis should not be made if CDKN2A/B homozygous deletion is detected in the tumor.,
The differential diagnosis includes other BRAFV600E mutant tumors like pilocytic astrocytoma, ganglioglioma (GG), and pleomorphic xanthoastrocytoma (PXA) and histological mimics like IDH1 mutant DA and H3K27M mutant DA. PA comprises predominantly of bipolar hair like pilocytic cells with the presence of rosenthal fibers and/or eosinophilic granular bodies. GG is characterized by an obvious dysplastic neuronal component. PXA is composed of pleomorphic tumor cells including large multinucleated cells and xanthomatous cells along with the presence of eosinophilic granular bodies and reticulin deposition. IDH1 mutant DA and H3K27M mutant DA can be differentiated by the presence of IDH1 or histone 3 mutation.
| Approach to Diagnosis|| |
In addition to histomorphology, detailed clinical history and radiology should be evaluated in all cases with provisional diagnosis of pDLGG. In addition to the tumor-specific radiological features, the status of the tumor circumscription is vital for the pathological diagnosis, especially in cases of small biopsies.
A wide range of testing platforms are available for routine assessment in clinical laboratories. However, the WHO working group has not recommended any particular method. Some laboratories are already implementing a comprehensive approach based on next-generation sequencing or methylation profiling to classify pDLGGs. This strategy is currently not feasible from a cost and logistic point of view in resource-limited countries. Based on the relatively high prevalence of these alterations in specific locations and histologies, a rational approach using more cost-effective testing platforms (Immunohistochemistry, Sanger sequencing, FISH, Real-time PCR, Nanostring counter, etc) can be optimized to minimize time and cost [Table 2], [Figure 3]. The choice of method depends upon available infrastructure, robustness, throughput of the techniques, and expertise.
|Table 2: Association of histological features with different molecular alterations|
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|Figure 3: Suggested approach for diagnosis of pDLG (AG-angiocentric glioma, DA-diffuse astrocytoma, pOG-pediatric type oligodendroglioma)|
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In instances of probable diagnosis of pDLGG, if molecular testing is unavailable, the default diagnosis would be “diffuse astrocytoma” or “oligodendroglioma,” “not otherwise specified” (NOS). If molecular testing fails to discover any of genetic alterations that would classify a diffuse glioma among the enlisted entities, the default diagnosis would be “diffuse astrocytoma” or “oligodendroglioma,” “not elsewhere classified” (NEC).
| Conclusions|| |
Current neuro-oncological practice is increasingly emphasizing on the integration of histopathologic data and molecular alterations for layered reporting of brain tumors. The identification of driver mutations in pediatric gliomas has highlighted the biological and clinicopathological heterogeneity and opened new therapeutic avenues. The role of these genetic alterations in pLGGs is valuable from diagnostic, prognostic, and therapeutic perspectives. Sequential testing of genetic alterations based on the layered integrated approach while considering the histology, location, and genetic information is highly recommended. Altogether rich and useful data obtained with careful morphologic analysis, judicious use of immunohistochemical stains, FISH and Sanger sequencing technologies can have an important impact not only on prognosis but also on appropriate management.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ostrom QT, de Blank PM, Kruchko C, Petersen CM, Liao P, Finlay JL, et al
. Alex's Lemonade Stand foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 2015;16(Suppl 10):x1-36.
Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol 2018;20:iv1-86.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System (Revised 4th
ed). Lyon: IARC; 2016.
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al
. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.
Lefkowitz IB, Packer RJ, Sutton LN, Siegel KR, Bruce DA, Evans AE, et al
. Results of the treatment of children with recurrent gliomas with lomustine and vincristine. Cancer 1988;61:896-902.
Lassaletta A, Scheinemann K, Zelcer SM, Hukin J, Wilson BA, Jabado N, et al
. Phase II weekly vinblastine for chemotherapy-naïve children with progressive low-grade glioma: A Canadian pediatric brain tumor consortium study. J Clin Oncol 2016;34:3537-43.
Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, et al
. Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell 2020;37:569-83.e5.
Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun 2020;8:30.
Ellison DW, Hawkins C, Jones DTW, Onar-Thomas A, Pfister SM, Reifenberger G, et al
. cIMPACT-NOW update 4: Diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol 2019;137:683-7.
Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, et al
. International Society of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014;24:429-35.
Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, et al
. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013;45:602-12.
Ramkissoon LA, Horowitz PM, Craig JM, Ramkissoon SH, Rich BE, Schumacher SE, et al
. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci USA 2013;110:8188-93.
Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, et al
. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 2016;131:833-45.
Bale TA. FGFR- gene family alterations in low-grade neuroepithelial tumors. Acta Neuropathol Commun 2020;8:21.
Chiang J, Harreld JH, Tinkle CL, Moreira DC, Li X, Acharya S, et al
. A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration. Acta Neuropathol 2019;138:1091-2.
Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R, et al
. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 2016;48:273-82.
Dandapath I, Chakraborty R, Kaur K, Mahajan S, Singh S, Sharma MC, et al
. Molecular alterations of low-grade gliomas in young patients: Strategies and platforms for routine evaluation. Neurooncol Pract 2021;8:652-61.
Gao R, Cao C, Zhang M, Lopez MC, Yan Y, Chen Z, et al
. A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets. Oncotarget 2014;5:12528–42.
Tatevossian RG, Tang B, Dalton J, Forshew T, Lawson AR, Ma J, et al
. MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol 2010;120:731–43.
Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004;6:313-9.
Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K, et al
. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008;68:8673-7.
Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, et al
. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol 2017;35:2934-41.
Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al
. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): An epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 2017;133:417-29.
Tosuner Z, Geçer MÖ, Hatiboğlu MA, Abdallah A, Turna S. BRAF V600E mutation and BRAF VE1 immunoexpression profiles in different types of glioblastoma. Oncol Lett 2018;16:2402–8.
Horbinski C. To BRAF or not to BRAF: Is that even a question anymore? J Neuropathol Exp Neurol 2013;72:2–7.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al
. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16.
Dai S, Zhou Z, Chen Z, Xu G, Chen Y. Fibroblast Growth Factor Receptors (FGFRs): Structures and small molecule inhibitors. Cells 2019;8:614.
Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ, et al
. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013;45:927–32.
Rivera B, Gayden T, Carrot-Zhang J, Nadaf J, Boshari T, Faury D, et al
. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 2016;131:847-63.
Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al
. AZD4547: An orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 2012;72:2045–56.
Wang M, Tihan T, Rojiani A, Rojiani AM, Bodhireddy SR, Prayson RA, et al
. Monomorphous angiocentric glioma: A distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 2005;64:875-81.
Burger PC, Juvet A, Presusser M, Hans VH, Rosenblum MK, Lellouch-Tubiana A. Angiocentric glioma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. 4th
ed. Lyon, FR: IARC Press; 2007. p. 92-3.
Weaver KJ, Crawford LM, Bennett JA, Rivera-Zengotita ML, Pincus DW. Brainstem angiocentric glioma: Report of 2 cases. J Neurosurg Pediatr 2017;20:347-51.
Han G, Zhang J, Ma Y, Gui Q, Yin S. Clinical characteristics, treatment and prognosis of angiocentric glioma. Oncol Lett 2020;20:1641-8.
Adamek D, Siwek GP, Chrobak AA, Herman-Sucharska I, Kwiatkowski S, Morga R, et al
. Angiocentric glioma from a perspective of A-B-C classification of epilepsy associated tumors. Folia Neuropathol 2016;54:40-9.
Fuller LD, Prayson RA. Molecular immunohistochemical profile of angiocentric glioma. J Epilepsy Res 2020;10:79-83.
Buccoliero AM, Castiglione F, Degl'innocenti DR, Moncini D, Spacca B, Giordano F, et al
. Angiocentric glioma: Clinical, morphological, immunohistochemical and molecular features in three pediatric cases. Clin Neuropathol 2013;32:107-13.
Chen Y, Tian T, Guo X, Zhang F, Fan M, Jin H, et al
. Polymorphous low-grade neuroepithelial tumor of the young: Case report and review focus on the radiological features and genetic alterations. BMC Neurol 2020;20:123.
Bitar M, Danish SF, Rosenblum MK. A newly diagnosed case of polymorphous low-grade neuroepithelial tumor of the young. Clin Neuropathol 2018;37:178–81.
Gupta VR, Giller C, Kolhe R, Forseen SE, Sharma S. Polymorphous low-grade neuroepithelial tumor of the young: A case report with genomic findings. World Neurosurg 2019;132:347–55.
Sumdani H, Shahbuddin Z, Harper G, Hamilton L. Case Report of rarely described polymorphous low-grade neuroepithelial tumor of the young and comparison with oligodendroglioma. World Neurosurg 2019;127:47–51.
Riva G, Cima L, Villanova M, Ghimenton C, Sina S, Riccioni L, et al
. Low-grade neuroepithelial tumor: Unusual presentation in an adult without history of seizures. Neuropathology 2018;38:557–60.
Wefers AK, Stichel D, Schrimpf D, Coras R, Pages M, Tauziède-Espariat A, et al
. Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course. Acta Neuropathol 2020;139:193-209.
Professor of Neuropathology, Neurosciences Centre, All India Institute of Medical Sciences, Ansari Nagar - 110029, New Delhi
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]