Recurrent symptomatic intracranial hemorrhage in high-grade astrocytoma with piloid features: illustrative case

Abstract

BACKGROUND

High-grade astrocytoma with piloid features (HGAP) is a novel condition introduced in the 2021 World Health Organization classification. Given that it has been recently classified, reports clarifying its clinical features or diagnostic criteria are lacking, especially in cases of atypical presentation. Herein, the authors present a rare case of HGAP with repeated symptomatic hemorrhages.

OBSERVATIONS

A woman in her 20s presented with an acute headache and vertigo. Computed tomography and magnetic resonance imaging revealed a 2.5 × 2.8 × 2.3–cm hemorrhagic cerebellar mass with calcifications. After moderate improvement of her symptoms, she developed recurrent hemorrhage, and the tumor size increased (3.0 × 3.6 × 4.0 cm) 18 days later, necessitating resection. Pathological and molecular analyses confirmed the diagnosis of HGAP with an FGFR1-TACC1 fusion, MTAP/CDKN2A/B deletion, and SETD2 rearrangement. Radiologically, the presence of calcification and cystic components and the absence of perilesional edema were atypical features of previously reported HGAP.

LESSONS

Although recurrent symptomatic intracranial hemorrhages are rare in HGAP, enhancing lesions on magnetic resonance imaging suggest the need for resection to obtain tissue for molecular diagnosis and guide adjuvant treatment strategies.

https://thejns.org/doi/10.3171/CASE24395

High-grade astrocytoma with piloid features (HGAP) is a novel entity defined by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW)¹ in the 2021 World Health Organization (WHO) classification as an astrocytoma exhibiting piloid cytology with anaplastic features, frequent mitogen-activated protein kinase (MAPK) pathway alterations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletions, and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations or loss.¹ HGAP occurs predominantly in the cerebellum and can develop de novo or through low-grade lesions, often harboring neurofibromatosis type 1 (NF1), B-Raf proto-oncogene (BRAF), or fibroblast growth factor receptor 1 (FGFR1) mutations. Its prognosis is considered intermediate between those of pilocytic astrocytomas (PAs) and glioblastomas.² Furthermore, patients with NF1, a genetic disorder that accounts for 9% of HGAP cases, exhibit worse progression-free survival.³

Case reports with confirmed diagnoses are limited, and further research is needed to validate the clinical behavior of HGAP. The aim of this report was to present the clinical course of an exceedingly rare case of HGAP with repeated symptomatic hemorrhage and discuss the implications of this atypical presentation.

Illustrative Case

Presentation and Neuroimaging Findings

A woman in her 20s without NF1 was admitted after presenting with an acute-onset throbbing headache and rotatory vertigo. Neurological examinations revealed no focal deficits. Computed tomography (CT) and magnetic resonance imaging (MRI) at admission revealed a 2.5 × 2.8 × 2.3–cm hemorrhagic mass with calcifications in the left cerebellar hemisphere (Fig. 1A– D). Digital subtraction angiography of the right vertebral artery revealed hypovascularity of the tumor bed (Fig. 1E). The patient was managed conservatively, as her symptoms spontaneously resolved.

FIG. 1.

Neuroimaging at initial presentation. A: CT revealed a hemorrhagic calcified mass lesion in the left cerebellar hemisphere. B: T2-weighted MRI delineating a mixed-signal-intensity (iso-high) cerebellar tumor with a cystic component. C: The mass demonstrated an isointense signal on T1-weighted MRI. D: Axial postgadolinium T1-weighted MRI revealed heterogeneous enhancement. E: Vertebral angiography revealed hypovascularity of the tumor bed.

However, 18 days later, she developed recurrent sudden-onset headache, nausea, vertigo, and truncal ataxia. Repeated CT and MRI showed hemorrhage recurrence, leading to an increase in the size of the mass to 3.0 × 3.6 × 4.0 cm. In addition, the scans revealed an enlarged cystic component and increased edema around the hemorrhage (Fig. 2A and B). The patient underwent urgent resection for the recurrent hemorrhages, leading to neurological deficits.

FIG. 2.

Neuroimaging at the second hemorrhagic presentation and postresection follow-up. A: Repeat CT showing the evolution of the intratumoral hemorrhage. B: Gadolinium-enhanced T1-weighted MRI confirmed rebleeding within the enhancing tumor. C: Postoperative MRI showing gross-total resection of the lesion, with preservation of the surrounding vasculature (arrow).

Surgical Findings

An occipital transtentorial approach in the park-bench position was chosen because of the tumor’s location in the superior portion of the cerebellum, adjacent to the tentorium. Neuronavigation was used for tumor resection. The tumor border with the cerebellum was relatively clear, and many feeders required coagulation. The strategy was to aspirate the tumor and expose the normal cerebellum. The tumor had a grayish-translucent soft portion (Fig. 3A) and calcified hard areas (Fig. 3B). Consistent with the MRI findings, an intratumoral hemorrhage was observed (Fig. 3C). After gross-total resection was confirmed (Fig. 3D), the exposed fourth ventricle wall was reconstructed with fibrin glue–fixed oxidized cellulose to prevent cerebrospinal fluid leakage. The patient had an uneventful postoperative course, with no new neurological deficits.

FIG. 3.

Intraoperative photographs. A: Part of the tumor was grayish-translucent and soft (white arrowheads). B: The tumor had a hard calcified portion. C: Intratumoral hemorrhage was observed. D: After gross-total resection, the fourth ventricle (white arrow) was detected.

Pathological and Genetic Findings

Final pathological examination revealed a high-cellularity glial neoplasm composed of monomorphic cells with marked nuclear atypia. Hematoxylin and eosin staining revealed eosinophilic granular bodies, Rosenthal fibers, thin-walled ectatic blood vessels, and hyalinization (Fig. 4A–E). The MIB-1 labeling index was 10% with brisk mitotic activity. Loss of nuclear ATRX expression was also observed. Subsequent cancer genomic profiling identified an FGFR1–transforming acidic coiled-coil-containing protein 1 (TACC1) fusion and homozygous deletions of methylthioadenosine phosphorylase (MTAP) and CDKN2A/B, among other mutations. DNA methylation profiling confirmed the diagnosis of HGAP with a high prediction score of 0.94 on the German Cancer Research Center (DKFZ) classifier (Fig. 4F).

FIG. 4.

Histopathological features. A: Hematoxylin and eosin (H&E) staining under a low-power field (bar = 100 μm) exhibits marked hypercellularity and nuclear atypia with piloid cells. BandC: H&E staining under a high-power field (bar = 20 μm) reveals eosinophilic granular bodies (white arrows) and Rosenthal fibers (white arrowhead) within the neoplastic astrocytes. D: H&E staining showing thin-walled ectatic blood vessels (bar = 100 μm). E: H&E staining showing hyalinization (bar = 100 μm). F: Copy number analysis indicates a homozygous CDKN2A/B deletion, and the black arrow in the figure indicates CDKN2A/B.

The patient was diagnosed with HGAP based on molecular examination. To determine the appropriate treatment, genetic profiling using OncoGuide NCC Oncopanel was performed, and 6 potentially treatment-relevant genetic variants were identified: CDKN2A loss, CDKN2B loss, FGFR1-TACC1 fusion (F18*; T7, where F18* indicates fusion at the full exon 18 of FGFR1 and T7 indicates joining at exon 7 of TACC1), FGFR rearrangement exon 18, MTAP loss, and SET domain containing 2 (SETD2) rearrangement exon 17. In the absence of an established standard treatment for HGAP, FGFR tyrosine kinase inhibitors were considered the most promising potential treatment option based on the molecular findings. However, as no residual tumor was visible on postoperative imaging, the patient did not meet the current eligibility criteria for immediate targeted therapy. She was placed under observation with a plan for close follow-up, allowing for prompt initiation of treatment should any signs of recurrence be detected.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

HGAP is a recently classified tumor entity. Since its inclusion, only 2 studies have reported imaging findings. These studies included 14 patients (6 patients in one study and 8 patients in the other;^{4, 5} Table 1). Consistent with these studies, our patient exhibited hypointense signals on T1-weighted imaging, hyperintense signals on T2-weighted imaging, and heterogeneous contrast enhancement. In contrast, our case uniquely demonstrated the presence of calcification and a cystic component, which have not been reported in prior studies. While some cases in the literature show perilesional edema and diffusely infiltrating margins, our patient lacked perilesional edema and exhibited well-defined tumor margins.

TABLE 1.

Literature review of cases including radiographic findings of HGAP

Authors & Year	Age (yrs), Sex	Tumor Location	T1WI	T2WI	DWI	Gd Enhancement on T1WI	Hemorrhage	Other Remarkable Features	NF1	Op	Adjuvant Therapy
Bender et al., 20214	71, M	Spinal cord (T12)	Hypo-/isointense	Hyperintense		Tumor rim enhancement w/ lack of central enhancement	No	No	No	STR→GTR	RT (54 Gy), TMZ (4 cycles after reresection)
	49, F	Pons rt cerebellar peduncle	Hypo-/isointense	Hyperintense	No restriction	Mild patchy contrast enhancement	No	No	No	Stereotactic biopsy	RT (54 Gy), TMZ followed by PCV
	67, M	Spinal cord (T2–5)	Hypo-/isointense	Hyperintense	NA	Tumor rim enhancement w/ lack of central enhancement	No	No	No	STR	NA
	53, M	Brainstem	Hypo-/isointense	Hyperintense	NA	NA	No	No	No	STR	RT (54 Gy)
	47, M	Mesencephalon-diencephalon	Hypo-/isointense	Hyperintense	No restriction	Patchy contrast enhancement	No	No	Yes	Stereotactic biopsy	No
	44, M	Rt parieto-occipital cerebrum	Hypo-/isointense	Hyperintense	No restriction	Tumor rim enhancement w/ lack of central enhancement	No	No	Yes	STR→STR	RT (59.2 Gy), TMZ followed by binimetinib
Soni et al., 20245	44, M	Intramedullary T9–10	Hypointense	Hyperintense	No restriction	Plaque-like enhancement	No	No	No	GTR	TMZ, RT
	42, M	Midline pontomesencephalic	Hypointense	Hyperintense	No restriction	Peripheral, irregular enhancement w/ central necrosis	No	No	No	No	Chemoradiation (details unknown)
	74, M	Intramedullary C5–T1	Hypointense	Hyperintense	No restriction	Heterogeneous enhancement	No	No	Yes	GTR	TMZ, RT
	38, F	Lt cerebellum	Hypointense	Hyperintense	No restriction	Multicystic lesion w/ peripheral enhancement	Yes	Multicystic lesion	No	GTR	TMZ, RT
	44, M	Pontomedullary	Hypointense	Hyperintense	Patchy restriction	Enhancement-like, minimal, patchy, ill-defined	No	No	Yes	No	Chemoradiation (details unknown)
	32, F	Pons–cerebellopontine angle	Hypointense	Hyperintense	No restriction	Heterogeneous enhancement	No	No	Yes	STR	TMZ, RT
	19, M	Midline diencephalic-thalamic region	Hypointense	Hyperintense	No restriction	Peripheral, irregular enhancement w/ central necrosis	Yes	No	No	STR	No
	71, F	Midline diencephalic-thalamic region	Hypointense	Hyperintense	No restriction	Peripheral, irregular enhancement w/ central necrosis	Yes	No	No	STR	TMZ, RT
Present case	20s, F	Lt cerebellum	Hypo-/isointense	Hyperintense	No restriction	Heterogeneous enhancement	Repeated	Cyst calcification	No	GTR	No

DWI = diffusion-weighted imaging; Gd = gadolinium; GTR = gross-total resection; NA = not available; PCV = procarbazine; RT = radiotherapy; STR = subtotal resection; T1WI = T1-weighted imaging; T2WI = T2-weighted imaging.

The imaging findings in our case shared several similarities with the typical appearance of cavernous malformations (CMs), including the presence of a cystic component, intralesional hemorrhage, and calcification.^6–10 The key differentiating points include the rarity of contrast enhancement in CMs,¹¹ whereas HGAP often demonstrates heterogeneous or peripheral irregular enhancements. Additionally, a hypointense rim on T2-weighted imaging surrounding the central region is a common finding in CMs,¹² but it is less frequently observed in HGAP.

Among all 15 reported HGAP cases, including ours, 4 demonstrated evidence of hemorrhage (Table 1). However, our case is the only one to exhibit repeated symptomatic intracranial hemorrhage. This is commonly caused by hypertension, amyloid angiopathy, brain tumors, vascular malformations, or trauma.^{13, 14} Brain tumors are responsible for 0.6%–18% of all intracranial hemorrhages, with the highest incidence in malignant tumors, such as metastatic brain tumors (2.9%–36%) and glioblastoma (3.7%–7.2%). In contrast, benign tumors such as low-grade gliomas have a significantly lower risk of intratumoral hemorrhage (< 1%).^14–17 However, spontaneous hemorrhage has been reported in 8% of PAs,¹⁷ despite being classified as grade I tumors under the WHO classification.¹⁸ PAs have various factors that contribute to bleeding, such as tumor growth rate, vascular invasion, necrosis, coagulation abnormalities, and structural features of the tumor vasculature, including thin-walled ectatic blood vessels and degenerative mural hyalinization,¹⁹ which were observed in our case. Research on glioma-induced angiogenesis has shown that glioblastomas and PAs overexpress vascular endothelial growth factor, which occurred in response to regional tissue hypoxia, correlated with vascular alterations, and induced intratumoral hemorrhage in an experimental glioblastoma model.^20–24

In the present case of HGAP with recurrent hemorrhage and calcification, the mechanisms of bleeding were similar to those observed in PAs and glioblastomas. The presence of calcification, as noted in 27% of PAs with hemorrhage,¹⁷ could be a predisposing factor for bleeding.

Although this is the first case report of HGAP with repeated symptomatic hemorrhage, bleeding may not be rare in this type of tumor. Cases with clinical courses^{4, 5} similar to ours highlight the importance of obtaining specimens for both histopathological and molecular diagnoses.

The standard treatment for HGAP after initial therapy remains unestablished. While temozolomide (TMZ) and radiotherapy are frequently considered for high-grade gliomas, their efficacy in HGAP remains unclear. Some reports suggest that HGAP with ATRX mutations may have increased sensitivity to DNA-damaging agents such as TMZ²⁵ and that radiotherapy may be effective in cerebellar high-grade gliomas with a lower frequency of epidermal growth factor receptor amplification.^26–29

Various molecular targeted drugs have been reported as potential therapies for HGAP.^29–34 In our case, genomically targeted therapy was considered based on the genetic profiling results from the OncoGuide NCC Oncopanel. The detected alterations, including FGFR1-TACC1 rearrangement, MTAP/CDKN2A/B deletion, and SETD2 rearrangement, suggested FGFR inhibitors as a potential treatment option. However, the patient did not meet the eligibility criteria for immediate targeted therapy due to the absence of a residual tumor. Moreover, many FGFR inhibitor trials exclude concurrent radiation therapy, further limiting immediate treatment options.

Given these considerations, we decided to closely monitor the patient and initiate FGFR inhibitor treatment promptly upon detection of any recurrence. While targeted therapies show promise for HGAP, their efficacy remains to be fully established, necessitating further research on the correlation between genetic alterations and treatment sensitivity in this tumor type.

Lessons

The presence of an enhancing mass lesion with recurrent symptomatic intracranial hemorrhage, although rare in HGAP, warrants its consideration and is a strong indication for resection. Obtaining tissues for molecular diagnosis is crucial to confirm the diagnosis of HGAP and guide appropriate adjuvant treatment strategies.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Kato, Niwa. Acquisition of data: Kato, Niwa, Ohka, Hirato, Sasaki, Ichimura, Kageyama, Oishi. Analysis and interpretation of data: Kato, Niwa, Kuwabara, Ohka, Hirato, Sasaki, Ichimura. Drafting the article: Kato, Niwa, Hasegawa. Critically revising the article: Kato, Hasegawa. Reviewed submitted version of manuscript: Niwa, Hasegawa, Sasaki, Ichimura, Saito. Approved the final version of the manuscript on behalf of all authors: Kato. Administrative/technical/material support: Yoshioka, Mizuno. Study supervision: Naito, Saito. Histopathological and integrated diagnoses: Kuwabara, Hirato, Sasaki, Ichimura, Yoshioka.

Correspondence

Takenori Kato: Komaki City Hospital, Komaki, Aichi, Japan. neuro.kato@gmail.com.