High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

Abstract

Purpose: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity.

Methods: During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected.

Results: Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes.

Conclusions: Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

Keywords: Anaplastic astrocytoma with piloid features; Case series; HGAP; High-grade astrocytoma with piloid features; MC AAP; Methylation-based classification.

Fig. 1

T-SNE analysis of DNA methylation data of the six high-grade astrocytomas with piloid features (HGAP) of this series together with a reference cohort of 11 different molecular tumor classes (n = 616) [2]. The six cases clearly group together with the reference cohort of HGAP. Reference methylation classes: HGAP High-grade astrocytoma with piloid features (16 cases); DLGNT diffuse leptomeningeal glioneuronal tumor (6 cases); DMG K27 diffuse midline glioma, H3 K27M mutant (78 cases); GBM G34 glioblastoma, IDH wild-type, H3 G34 mutant (41 cases); GBM MES glioblastoma, IDH wild-type, subclass mesenchymal (56 cases); GBM RTK I glioblastoma, IDH wild-type, subclass RTK I (64 cases); GBM RTK II glioblastoma IDH wild-type, subclass RTK II (138 cases); LGG PA GG ST low-grade glioma, subclass hemispheric pilocytic astrocytoma and ganglioglioma (24 cases); LGG PA MID low-grade glioma, subclass midline pilocytic astrocytoma (38 cases); LGG PA PF low-grade glioma, subclass posterior fossa pilocytic astrocytoma (114 cases); PXA (anaplastic) pleomorphic xanthoastrocytoma (35 cases)

Fig. 2

Hematoxylin–eosin stainings and copy number plots. Patient 1 Hematoxylin–eosin staining revealed low cell density astroglial tumor without marked proliferation. Genome-wide DNA methylation analysis: HGAP (score: 0.99), copy number analysis demonstrated homozygous CDKN2A/B deletion and a complex structural rearrangement of the FGFR1 locus, possibly indicating a gene fusion. The MGMT promoter was non-methylated. Patient 2 Hematoxylin–eosin staining revealed a moderately cell dense, pleomorphic glial tumor without necrosis, vascular proliferation or marked mitotic activity. The Ki67 proliferation index was focally up to 5% and a nuclear ATRX loss was noted. DNA methylation profiling revealed an HGAP (score: 0.98). Copy number analysis demonstrated homozygous CDKN2A/B deletion. MGMT promoter was non-methylated. Patient 3 Hematoxylin–eosin staining revealed a low to moderately cell rich, moderately pleomorphic glial tumor with vascular proliferation. Necrosis or mitotic activity was not observed. Ki67 proliferation index was 5–10% and a nuclear ATRX loss was noted. DNA methylation profiling revealed the diagnosis of an HGAP (score: 0.96). Copy number analysis demonstrated homozygous CDKN2A/B deletion. MGMT promoter was non-methylated. Patient 4 Hematoxylin–eosin staining revealed a moderately cell rich, moderately pleomorphic glial tumor without vascular proliferation, necrosis or mitotic activity. The Ki67 proliferation index was focally up to 5% and ATRX was retained. The DNA methylation profile was not classifiable but showed the highest classifier score for HGAP (score: 0.61). Copy number analysis demonstrated homozygous CDKN2A/B deletion. The MGMT promoter was methylated. The tumor was IDH 1/2, H3F3A and BRAF V600 wild-type. Patient 5 Hematoxylin–eosin staining a moderately cell rich, moderately pleomorphic glial tumor without vascular proliferation, necrosis or mitotic activity. The Ki67 proliferation index was 5% and nuclear ATRX was lost. Genome-wide DNA methylation analysis confirmed the diagnosis of an HGAP (score: 0.85). Copy number analysis demonstrated homozygous CDKN2A/B deletion. The MGMT promoter was non-methylated. Patient 6 Hematoxylin–eosin staining revealed a moderately cell rich, malignant glial tumor with vascular proliferation, necrosis, mitotic activity and vascular thrombi. The Ki67 proliferation index was 10% to 15% and ATRX was retained. The DNA methylation profile was not classifiable but showed the highest classifier score for HGAP (score: 0.58). Copy number analysis demonstrated homozygous CDKN2A/B deletion. The MGMT promoter was methylated. The tumor was IDH 1/2, H3F3A and BRAF V600 wild-type. CDKN2A/B cyclin-dependent kinase inhibitor 2A/B, FGFR1 fibroblast growth factor receptor 1

Fig. 3

Clinical course of six patients with high-grade astrocytoma with piloid features including pre-operative MRI (A–L) and O-(2-[¹⁸F]fluoroethyl)-l-tyrosine positron emission tomography (FET-PET) (C). FS fat saturation, Gd Gadolinium, Gy Gray, MPRAGE magnetization prepared rapid gradient echo, MRI magnetic resonance imaging, PCV procarbazine, lomustine, and vincristine, FET O-(2-[¹⁸F]fluoroethyl)-l-tyrosine, PET positron emission tomography, PFS progression-free survival, OS overall survival, RCTx radiochemotherapy, RT radiotherapy, STR subtotal resection, T thoracic vertebra, T1w T1 weighted image, T2w T2 weighted image, TMZ temozolomide