Circumscribed Astrocytic Gliomas

2024-10-31   Scott Ryall, PhD 

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

Circumscribed astrocytic gliomas are defined by their characteristic solid growth pattern as compared to diffuse glial tumors. 1 Circumscribed astrocytic gliomas include: i) pilocytic astrocytoma, ii) high-grade astrocytoma with piloid features (HGAP), iii) pleomorphic xanthoastrocytoma (PXA), iv) subependymal giant cell astrocytoma (SEGA), and v) astroblastoma, MN1-altered.

Additional details are described in the 2021 WHO Classification of Tumors of the Central Nervous System.

Circumscribed Astrocytic GliomasGenetic Event(s)
Pilocytic astrocytomaPilocytic astrocytoma is the most common central nervous system tumor in children. 2 The approximate age at diagnosis is 10-12 years, despite a wide range of incidence (1-67 years). 2,3 The most frequent genetic abnormalities observed in pilocytic astrocytoma are rearrangements of approximately 2-Mb at chromosome 7q34 resulting in the KIAA1549::BRAF gene fusion involving various combinations of the KIAA1549 and BRAF exons. 4-7 Infrequently, alternate BRAF fusions have been observed 6,8-10, which, like KIAA1549::BRAF, all result in loss of the N-terminal regulatory domain of BRAF, leading to dysregulated MAPK signaling. 7,11,12 Other genetic abnormalities are in genes encoding other members of the MAPK pathway and include NF1 alterations (typically germline and associated with optic pathway glioma), BRAF mutations (most often p.V600E), FGFR1 mutations, FGFR1 fusions (most often FGFR1::TACC1), NTRK1/NTRK2/NTRK3 fusions, KRAS mutations, and RAF1 fusions. 7,11,13-15
High-grade astrocytoma with piloid featuresHigh-grade astrocytoma with piloid features (HGAP) is a newly defined molecular entity with a median age at diagnosis of 40 years (24-75 years) which is extremely rare in the pediatric demographic. 16-18 Currently, HGAP can only be diagnosed via DNA methylation profiling. 16,19 Despite this, certain genetic markers suggestive of the diagnosis include CDKN2A and/or CDKN2B homozygous deletions (~80%), ATRX mutations and/or loss of expression (45%), KIAA1549::BRAF (20%), NF1 mutations or deletions (~30%), FGFR1 mutations (~20%), KRAS mutations (~3%), and BRAF mutations (~1%). 16 Total or partial loss of chromosome 19q is observed in approximately 50% of HGAP. 16,19
Pleomorphic xanthoastrocytomaPleomorphic xanthoastrocytoma (PXA) is diagnosed across a wide range of ages with a median of approximately 25 years (0-85 years). 20-22 All PXA harbor activating genetic alterations in a MAPK pathway gene. The most frequent of these is BRAF p.V600E which is seen in up to 80% of tumors. 7,23,24 >90% of BRAF p.V600E tumors have combined homozygous deletions of CDKN2A and/or CDKN2B. 23,25-27 Less frequently, these tumors may harbor TERT promoter mutations or amplifications. 23,28 Tumors without BRAF p.V600E can harbour a wide variety of alternative alterations in the MAPK pathway including non-canonical BRAF mutations and fusions, NTRK1/NTRK2/NTRK3 fusions, and NF1 alterations. Rare alterations in SMARCB1, BCOR, ARID1A,ATRX, PTEN, FANCA, PRKDC, NOTCH2/NOTCH3/NOTCH4, and BCL6 have also been described, but their significance is, as of now, unclear. 23,26,29 DNA methylation analysis classifies PXA as its own entity, which my help alleviate diagnsotic concern in cases with ambiguous morphology or non-canonical genetics. 19
Subependymal giant cell astrocytomaThe median age at diagnosis of subependymal giant cell astrocytoma (SEGA) is approximately 8 years (0-51 years), with >80% being diagnosed in patients ≤20. 30-32 and is strongly associated with tuberous sclerosis OMIM:191100 OMIM:613254. These tumors commonly harbor biallelic inactivation of TSC1 or TSC2, with the second hit frequenty being a deletion or loss of heterozygosity. 33-35 SEGA in the absence of tuberous sclerosis have been reported, but it is unclear whether they harbor undetectable TSC1/TSC2 variants or alternative mechanisms of inactivation. 35,36 BRAF p.V600E has been infrequently reported in SEGA, although these findings are disputed. 14,35,37 DNA methylation analysis classifies SEGA as its own tumor entity. 19
Astroblastoma, MN1-alteredThe median age at diagnosis of astroblastoma, MN1-altered is approximately 15 years (0-40 years). 38,39 It is defined by structural rearrangements of MN1, most commonly as MN1::BEND2 fusions, although other rare fusion partners have been reported. 40-43 Typically, MN1 alterations do not co-occurr with secondary oncogenic alterations, however, a rare subset of tumors have been shown to also harbor CDKN2A homozygous deletions. 40,42 Cytogenetically, astroblastomas often harbor monosomy 16 and partial losses of 22q and X. 40-42,44 DNA methylation analysis shows that astroblastoma have a unique profile as compared to other tumors with astroblastomatous rosettes, which can be helpful in diagnostically differentiating these cases. 19

Article Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
1341850762021The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.Louis DN et al
2316750942019CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016.Ostrom QT et al
3316864392019Survival and Prognosis of Patients with Pilocytic Astrocytoma: A Single-Center Study.Park JH et al
4189741082008Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas.Jones DT et al
5183985032008BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.Pfister S et al
6193738552009Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas.Forshew T et al
7322892782020Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.Ryall S et al
8214245302011Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma.Cin H et al
9284485142017A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma.Tomić TT et al
10291416722017A novel GIT2-BRAF fusion in pilocytic astrocytoma.Helgager J et al
11238175722013Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.Jones DT et al
12235839812013Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.Zhang J et al
13177127322007Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma.Janzarik WG et al
14212747202011Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.Schindler G et al
15232228492013Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.Gutmann DH et al
16295645912018Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.Reinhardt A et al
17307869202019Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre.Jaunmuktane Z et al
18316770152020The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population.Gareton A et al
19295396392018DNA methylation-based classification of central nervous system tumours.Capper D et al
20228434502012Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis.Perkins SM et al
21253185872015Pleomorphic Xanthoastrocytoma: Natural History and Long-Term Follow-Up.Ida CM et al
22338980552021Predictors of outcome in pleomorphic xanthoastrocytoma.Dono A et al
23300515282019The genetic landscape of anaplastic pleomorphic xanthoastrocytoma.Phillips JJ et al
2432619301988Use of aspirin for prevention of cardiovascular disease--1981-82 to 1985-86: the Minnesota Heart Survey.Folsom AR et al
25264547672015BRAF mutation and anaplasia may be predictive factors of progression-free survival in adult pleomorphic xanthoastrocytoma.Tabouret E et al
26281813252018Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation.Vaubel RA et al
27304967962019Molecular features of pleomorphic xanthoastrocytoma.Zou H et al
28302408662018BRAF V600E, TERT, and IDH2 Mutations in Pleomorphic Xanthoastrocytoma: Observations from a Large Case-Series Study.Ma C et al
29326193052021Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?Vaubel R et al
30240539822013Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference.Northrup H et al
31313335632019Clinical Characteristics of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex.Jansen AC et al
32314280372019Newly Diagnosed and Growing Subependymal Giant Cell Astrocytoma in Adults With Tuberous Sclerosis Complex: Results From the International TOSCA Study.Jansen AC et al
3394037141997Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors.Henske EP et al
3490071041996Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma.Mizuguchi M et al
35292211452017Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations.Bongaarts A et al
36259785312015Subependymal giant cell astrocytoma in the absence of tuberous sclerosis complex: case report.Beaumont TL et al
37253461652015BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas.Lee D et al
38318634782020Spinal cord astroblastoma with an EWSR1-BEND2 fusion classified as a high-grade neuroepithelial tumour with MN1 alteration.Yamasaki K et al
39326017752020Central nervous system neuroepithelial tumors with MN1-alteration: an individual patient data meta-analysis of 73 cases.Chen W et al
40289606232018Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities.Wood MD et al
41289907082018Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement.Hirose T et al
42308764552019Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis.Lehman NL et al
43311112742019MN1 rearrangement in astroblastoma: study of eight cases and review of literature.Mhatre R et al
44269194352016New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.Sturm D et al

Citation

Scott Ryall

Circumscribed Astrocytic Gliomas

Atlas Genet Cytogenet Oncol Haematol. 2024-10-31

Online version: http://atlasgeneticsoncology.org/solid-tumor/209293