CNS & pituitary tumors
Gliomas, glioneuronal tumors and neuronal tumors
Other astrocytic tumors
High grade astrocytoma with piloid features (HGAP)
Editorial Board Member: P.J. Cimino, M.D., Ph.D.
Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.
Last author update: 13 May 2024
Last staff update: 13 May 2024
Copyright: 2024, PathologyOutlines.com, Inc.
PubMed Search: High grade astrocytoma with piloid features
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2Cite this page: d'Amati A, Gianno F, Antonelli M. High grade astrocytoma with piloid features (HGAP). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/CNStumorHGAP.html. Accessed April 29th, 2025.
Definition / general
- Circumscribed astrocytic glioma with high grade piloid or glioblastoma-like histological features and distinct DNA methylation profile
Essential features
- Recently recognized entity, included in the 2021 WHO classification of CNS tumors
- Circumscribed astrocytic glioma occurring throughout the entire CNS, mostly in the posterior fossa
- High grade histological features associated with piloid or glioblastoma-like morphology
- Distinct DNA methylation profile and MAPK pathway gene alterations, often associated with homozygous deletion (HD) of CDKN2A / CDKN2B or ATRX alterations
- CNS WHO grade currently not assigned (clinical behavior roughly similar to CNS WHO grade 3)
Terminology
- Anaplastic astrocytoma with piloid features (not recommended by CNS WHO 2021)
ICD coding
- ICD-O: 9421/3 - high grade astrocytoma with piloid features
- ICD-11: 2A00.0Y & XH6PH6 - other specified gliomas of brain & astrocytoma, NOS
Epidemiology
- Comprehensive epidemiological data currently not available
- Rare, ~1 - 3% of CNS tumors (Neuropathol Appl Neurobiol 2020;46:478, Acta Neuropathol Commun 2019;7:24, Nature 2018;555:469)
- Very rare in pediatric population (Lancet Child Adolesc Health 2020;4:121, Acta Neuropathol 2020;139:287)
- Median age: 40 years; range: 4 - 88 years (Acta Neuropathol 2018;136:273, Acta Neuropathol Commun 2019;7:24, Acta Neuropathol 2020;139:287)
- No sex predilection (Acta Neuropathol 2018;136:273, Acta Neuropathol Commun 2019;7:24, Acta Neuropathol 2020;139:287)
Sites
- Can occur anywhere in the CNS
- Posterior fossa, particularly cerebellum, is most common (74%) (Acta Neuropathol 2018;136:273)
- More rarely supratentorial (17%) or spinal (7%) (Acta Neuropathol 2018;136:273)
Pathophysiology
- Cell of origin is currently unknown
- 3 pathways are probably involved in the pathogenesis (Acta Neuropathol 2018;136:273)
- MAPK pathway gene alterations are likely the initiating event (driver mutation)
- Deregulation of retinoblastoma tumor suppressor protein cell cycle pathway by CDKN2A / CDKN2B inactivation (homozygous deletion) or occasionally CDK4 amplification
- Activation of telomere maintenance by ATRX alterations and rarely TERT promoter mutations
- Numerous chromosomal alterations and frequent structural aberrations (Acta Neuropathol 2018;136:273)
- Partial gains of 12q and 17q
- Losses of 1p and 8p
- Partial losses of 14 and 19q
Etiology
- Generally sporadic without significant known risk factors
- In some cases, may occur from pre-existing low grade astrocytic tumors (Acta Neuropathol 2018;136:273)
- Uncommon association with irradiation but no established etiological role (Acta Neuropathol 2018;136:273)
- Rarely reported in patients with NF1 gene alterations (Acta Neuropathol 2018;136:273, Acta Neuropathol 2023;145:71)
Clinical features
- Clinical signs and symptoms depend on tumor location
Diagnosis
- Magnetic resonance imaging (MRI), followed by stereotactic brain biopsy or surgical resection
- CNS WHO 2021 diagnostic criteria
- Essential
- Histological aspect of an astrocytic glioma
- DNA methylation profile of HGAP
- Desirable
- MAPK pathway gene alteration
- CDKN2A / CDKN2B HD or CDK4 amplification
- ATRX mutation or loss of nuclear expression
- Anaplastic histological features
- Essential
Radiology description
- MRI
- T1 hypointense / isointense, T2 hyperintense (J Neurooncol 2021;153:109)
- Mostly no diffusion restriction; peripheral irregular enhancement with central necrosis or mixed heterogeneous enhancement (AJNR Am J Neuroradiol 2024;45:468)
- Some tumors may show glioblastoma-like radiological features (i.e., ring enhancing mass) (J Neurooncol 2021;153:109)
Radiology images
Contributed by Antonio d'Amati, M.D.
T2 MRI of brain
T1 MRI of brain
Coronal FLAIR MRI of brain
Sagittal FLAIR MRI of brain
Prognostic factors
- Prognostic data are currently limited to a single retrospective study (Acta Neuropathol 2018;136:273)
- 5 year overall survival: 50%
- No prognostic association with high grade histological features (e.g., mitoses or necrosis)
- No prognostic association with MGMT promoter methylation status
- CNS WHO grade currently not assigned (clinical behavior roughly similar to CNS WHO grade 3)
Case reports
- 68 year old man presented with dizziness, double vision and an infratentorial cystic mass (Clin Neuroradiol 2024;34:279)
- 8 cases, mean age 45.5 years, with different locations and clinical presentations (AJNR Am J Neuroradiol 2024;45:468)
- 6 cases, mean age 55.2 years, with different locations and clinical presentations (J Neurooncol 2021;153:109)
Treatment
- Complete surgical resection, if possible, followed by adjuvant radiation and chemotherapy (J Neurooncol 2021;153:109, AJNR Am J Neuroradiol 2024;45:468)
Gross description
- Mostly well demarcated solid lesion
- Areas of cystic degeneration, necrosis or hemorrhage may be variably present
Gross images
Contributed by Antonio d'Amati, M.D.
Cerebellar surgical resection
Microscopic (histologic) description
- Histological features are very variable and not sufficient for diagnosis, without additional molecular testing
- Astrocytic glioma, with moderate cell density
- Predominantly solid / circumscribed tumor growth but possible invasion into the adjacent parenchyma
- Growth patterns (Acta Neuropathol 2018;136:273)
- Glioblastoma-like
- Pleomorphic xanthoastrocytoma-like
- Pilocytic astrocytoma-like (cells with hair-like piloid cytoplasmic processes)
- Eosinophilic granular bodies or Rosenthal fibers (~30% of cases) (Acta Neuropathol 2018;136:273)
- High grade histological features
- Mitoses (usually ≥ 1 mitoses/10 high power fields [HPF] of 0.55 mm in diameter) (Acta Neuropathol 2018;136:273)
- Microvascular proliferations (hypertrophy, multilayering or glomeruloid proliferations)
- Necrosis (~30% of cases) (Acta Neuropathol 2018;136:273)
Microscopic (histologic) images
Contributed by Francesca Gianno, M.D., Ph.D.
Piloid features
Spindle cells
Sheets of cells
Rosenthal fibers
Eosinophilic granular bodies
Pleomorphic cells
Myxoid background
GFAP
Olig2
ATRX
Low Ki67
High Ki67
p16
Virtual slides
Contributed by Francesca Gianno, M.D., Ph.D. and Antonio d'Amati, M.D.
Cerebellar lesion with piloid features
Cerebellar lesion with GBM-like appearance
Positive stains
- GFAP
- Olig2
- Ki67 variable (5 - 15%) (J Neurooncol 2021;153:109)
Negative stains
- IDH1 R132H
- ATRX (loss of nuclear expression in ~40% of cases) (Acta Neuropathol 2018;136:273)
- H3K27M (very rare positive cases) (Acta Neuropathol 2018;136:273)
Electron microscopy description
- Not routinely used for diagnostic purposes
Molecular / cytogenetics description
- Currently, DNA methylation profiling is the only method for establishing a definitive diagnosis of HGAP (Acta Neuropathol 2018;136:273)
- Various MAPK pathway gene alterations reported, in order of frequency (Acta Neuropathol 2020;139:287, Acta Neuropathol 2018;136:273)
- NF1 alterations
- KIAA1549::BRAF fusions
- FGFR1 alterations
- KRAS mutations
- BRAF mutations
- CDKN2A or CDKN2B homozygous deletion (80% of cases) (Acta Neuropathol 2018;136:273)
- Alternatively, CDK4 amplification (rarely)
- ATRX alterations (45% of cases) (Acta Neuropathol 2018;136:273)
- Alternatively, TERT promoter mutations (rarely)
- H3 K27M mutations (3% of cases); definitive classification of these cases yet to be established (Acta Neuropathol 2018;136:273)
- ~5% of HGAP cases harbor TP53 mutations (Acta Neuropathol 2023;145:71)
Molecular / cytogenetics images
Contributed by Simone Minasi, Ph.D. and Francesca Romana Buttarelli, Ph.D.
CDKN2A homozygous deletion
KIAA1549::BRAF fusion
Images hosted on other servers:
DNA methylation data
Copy number plots
Sample pathology report
- Brain, cerebellum, resection:
- Integrated diagnosis: high grade astrocytoma with piloid features (HGAP)
- Histologic diagnosis: astrocytic glioma, with high grade histologic features
- Immunohistochemical results
- GFAP+
- Olig2+
- IDH1 R132H-
- Loss of ATRX nuclear expression
- Ki67: 10%
- CNS WHO grade: not assigned
- Molecular information
- DNA methylation class: HGAP (score 0.99)
- NF1 mutation
- CDKN2A homozygous deletion
Differential diagnosis
- Diffuse gliomas (including glioblastoma, IDH wild type; astrocytoma, IDH mutant; diffuse midline glioma, H3 K27 altered):
- Diffusely infiltrative
- Piloid features, eosinophilic granular bodies or Rosenthal fibers uncommon
- Distinct molecular features
- Pleomorphic xanthoastrocytoma:
- Most commonly localized in superficial cerebral cortex
- Reticulin deposition
- Expression of CD34 and neuronal antigens
- Frequent BRAF p.V600E mutations (very rare in HGAP)
- Pilocytic astrocytoma:
- High grade histologic features usually absent (if present: in the pediatric population, favor anaplastic pilocytic astrocytoma; in adult population, favor HGAP)
- Preserved ATRX expression (loss in 45% of HGAP cases)
- Distinct molecular alterations (some HGAP cases may have KIAA1549::BRAF fusions)
- Distinct DNA methylation profile
Additional references
Practice question #1
A 43 year man has a cerebellar mass. Histologic features are shown in the image above. Immunohistochemistry revealed IDH1 R132H negativity and loss of ATRX nuclear expression. Molecular analyses only revealed NF1 mutation and CDKN2A homozygous deletion. What is the most likely diagnosis?
- Ganglioglioma
- Glioblastoma, IDH wild type
- High grade astrocytoma with piloid features (HGAP)
- Pilocytic astrocytoma
- Pleomorphic xanthoastrocytoma
Practice answer #1
C. High grade astrocytoma with piloid features (HGAP). The image shows an astrocytic glioma, with piloid aspects and high grade histologic features. Answer D is incorrect because pilocytic astrocytomas with high grade histologic features (anaplastic PA) are uncommon in adult population; moreover, ATRX loss and CDKN2A homozygous deletion exclude this diagnosis. Answers B and E are incorrect because glioblastoma, IDH wild type and pleomorphic xanthoastrocytoma are uncommon in cerebellar locations and usually show preserved ATRX expression. Answer A is incorrect because ganglioglioma shows different clinical, histological, immunohistochemical and molecular features.
Comment Here
Reference: High grade astrocytoma with piloid features (HGAP)
Comment Here
Reference: High grade astrocytoma with piloid features (HGAP)
Practice question #2
Which of the following is an essential molecular criterion to confirm a diagnosis of high grade astrocytoma with piloid features (HGAP)?
- ATRX alterations
- CDK4 amplification
- KIAA1549::BRAF fusions
- Specific DNA methylation profile
- TP53 mutations
Practice answer #2
D. Specific DNA methylation profile. According to 2021 CNS WHO criteria, demonstration of DNA methylation profile is mandatory to confirm a diagnosis of HGAP. Answers A, B and C are incorrect because while ATRX alterations, KIAA1549::BRAF fusions and CDK4 amplification are reported at variable frequency in HGAP, these only represent desirable criteria. Answer E is incorrect because TP53 mutations are not commonly associated with HGAP.
Comment Here
Reference: High grade astrocytoma with piloid features (HGAP)
Comment Here
Reference: High grade astrocytoma with piloid features (HGAP)
