Leptomeningeal Dissemination in TERT Promoter-mutant Anaplastic Pleomorphic Xanthoastrocytoma Responding to BRAF–MEK Inhibition: A Case Report

Ryota KITANO; Hiroaki NAGASHIMA; Hiroki GOTO; Shunsuke YAMANISHI; Masamitsu NISHIHARA; Kazuhiro TANAKA; Yoshihiro MURAGAKI; Takashi SASAYAMA

doi:10.2176/jns-nmc.2026-0094

Abstract

Pleomorphic xanthoastrocytoma is a rare brain tumor that frequently harbors the oncogenic BRAF V600E mutation. Approximately 28.6%-47% of high-grade pleomorphic xanthoastrocytomas are associated with TERT promoter mutation and leptomeningeal dissemination, for which no established treatment exists and the prognosis remains poor. Combination therapy with BRAF and MEK inhibitors has demonstrated efficacy in BRAF V600E–mutant brain tumors. We report a case of a 22-year-old man with a right temporal lobe tumor initially diagnosed as World Health Organization grade 2 pleomorphic xanthoastrocytoma after gross total resection. Two years later, the tumor recurred and underwent malignant transformation to World Health Organization grade 3 pleomorphic xanthoastrocytoma. At the third resection, pathological and genomic analyses confirmed BRAF V600E mutation together with TERT promoter mutation. Following chemoradiotherapy, spinal leptomeningeal dissemination developed. After spinal irradiation, dabrafenib plus trametinib was initiated, resulting in partial radiological response and symptomatic improvement. Although regrowth occurred 10 months after initiation of targeted therapy, the patient remains alive at the time of writing.

Here, we report a case of recurrent anaplastic BRAF V600E–mutant pleomorphic xanthoastrocytoma with leptomeningeal dissemination that showed a transient but clinically meaningful response to combined BRAF–MEK inhibition and spinal radiation therapy. In addition, this case raises the possibility of an association between TERT promoter mutation and leptomeningeal dissemination, although further studies are required to clarify this relationship.

Introduction

Pleomorphic xanthoastrocytomas (PXAs) account for fewer than 0.3% of primary intracranial tumors.¹⁾ They typically occur in adolescents and young adults under 30 years of age and often present with seizures. PXAs are usually superficial supratentorial tumors, most commonly arising in the temporal lobe.²⁾ According to the World Health Organization 2021 Classification of Tumors of the Central Nervous System (CNS WHO), most PXAs are grade 2 tumors, while up to one-third are grade 3, characterized by anaplastic morphology, increased mitotic activity, and necrosis, with 5-year overall survival rates of only 51%-57%.²^-⁴⁾

Genetically, nearly all PXAs have the combination of RAF alterations, especially BRAF V600E, and CDKN2A/B homozygous deletion.⁵^,⁶⁾ Approximately 65%-75% of PXAs are known to harbor BRAF V600E mutation.⁷⁾CDKN2A homozygous deletion is observed in all high-grade PXAs.⁵⁾ Conversely, TERT promoter mutation is associated with a more aggressive biologic behavior and present in 28.6%-47% of high-grade PXAs,⁵^,⁸⁾ which suggested an association with malignant transformation.⁶⁾ Leptomeningeal dissemination (LMD) has been reported in approximately 20% of high-grade PXAs⁴^,⁹⁾ and is associated with poor outcome. The risk factors of dissemination have not been well characterized. Recently, BRAF–MEK inhibitor therapy has shown promising results in selected BRAF V600E–mutant gliomas.¹⁰^,¹¹⁾ However, evidence regarding its efficacy in disseminated high-grade PXAs remains limited. Furthermore, the molecular factors associated with dissemination in PXAs are not well established.

Herein, we report a case of recurrent anaplastic BRAF V600E–mutant PXA with LMD that showed a transient but clinically meaningful response to combined BRAF–MEK inhibition and spinal radiation therapy. This case also suggests a possible association between TERT promoter mutation and LMD.

Case Presentation

A 22-year-old man presented with seizures and was initially treated at another hospital. Magnetic resonance imaging (MRI) revealed a contrast-enhancing solid tumor in the right lateral temporal lobe (Figure 1A and B). He underwent right pterional craniotomy and gross total resection (Figure 1C) and was discharged without any neurological deficits. At that time, no evidence of neurological abnormalities or LMD was observed. Histopathological examination was consistent with CNS WHO 2016 grade 2 PXA.

Figure 1

Findings on neuroimaging at the initial presentation and at the time of the recurrence.

(A) A FLAIR image showing edema around the tumor. (B) An initial axial Gd T1-WI showing a solid heterogeneously enhancing tumor in the right temporal lobe. (C) A Gd T1-WI obtained after the first surgery showing gross subtotal resection. (D) A Gd T1-WI obtained at the time of the first recurrence showing residual tumor growth. (E) A Gd T1-WI obtained after the second surgery showing gross total resection. (F) A FLAIR image after the third surgery showing expanding cavity without surrounding edema. (G) A Gd T1-WI obtained at the time of the second recurrence showing regrowth of the tumor on the medial and posterior cavity wall. (H) A Gd T1-WI obtained after the third surgery—right temporal lobectomy—showing the residual tumor.

FLAIR: fluid-attenuated inversion recovery; Gd T1-WI: gadolinium-enhanced T1-weighted image

Two years later, tumor regrowth was detected (Figure 1D), and repeat gross total resection was performed (Figure 1E), demonstrating malignant transformation to WHO 2021 grade 3 PXA. One year after the second resection, MRI showed recurrent enhancement along the cavity wall (Figure 1F and G; Supplementary Figure 1A) without evidence of LMD, and the patient was referred to our institution for further management. A third craniotomy with right temporal lobectomy was performed. A portion of the medial lesion was left unresected because motor evoked potentials declined intraoperatively (Figure 1H). Postoperatively, the patient developed left upper quadrantanopia but had no motor or sensory deficits and was discharged with preserved functional status. Pathological examination revealed high-grade PXA harboring both BRAF V600E and TERT promoter mutations.

The patient subsequently received focal radiotherapy (60 Gy in 30 fractions) with concurrent temozolomide, followed by adjuvant temozolomide chemotherapy. During the third cycle of adjuvant therapy, he developed neck and shoulder pain. Spinal MRI and positron emission tomography demonstrated LMD confined to the spinal cord (Figure 2A-C), while no recurrence of the primary intracranial lesion was observed.

Figure 2

Images showing leptomeningeal dissemination.

Positron emission tomography (A) and Gd T1 (B, C) images revealed multiple lesions (arrow head) at the cervical and thoracic levels in the spinal cord. The lesions showed a partial response, and the patient’s symptoms improved after treatment with a BRAF–MEK inhibitor combination (D, E).

Gd T1: gadolinium-enhanced T1-weighted

The patient underwent spinal radiotherapy (35 Gy in 10 fractions), followed by targeted therapy with dabrafenib (300 mg/day in divided doses) and trametinib (2 mg/day). The treatment was well tolerated, with only a grade 1 rash according to the CTCAE version 5.0, which did not require additional management. His pain improved rapidly, and follow-up spinal MRI demonstrated a partial radiological response (Figure 2D and E). After initiation of targeted therapy, the patient was able to continue living at home with a good quality of life.

Eight months later, both intracranial and spinal LMD progressed, leading to rapidly progressive paraplegia over several days. Targeted therapy was discontinued, and intrathecal chemotherapy along with additional radiotherapy was administered. The patient remains alive 10 months after the initiation of targeted therapy.

Pathological and molecular findings

The initial specimen showed pleomorphic astrocytic and xanthomatous cells with low proliferative activity (MIB-1 ≤1%). Immunostaining showed that isocitrate dehydrogenase (IDH) and p53 were negative and ATRX expression was intact. TERT promoter mutation was not tested. These findings were consistent with grade 2 PXA.

The second specimen demonstrated a dense and relatively uniform proliferation of atypical astrocytic cells with spindle-shaped or glassy cytoplasm. Compared with the initial specimen, the degree of pleomorphism was slightly reduced. Small round atypical cells and pseudopapillary structures with decreased cellular cohesion were also observed. Although focal infiltrative features were present, no definite necrosis was identified. Increased mitotic activity (>5 mitoses/10 high-power fields [HPF]) and a Ki-67 labeling index of approximately 5% were noted. In addition, DNA sequencing identified a TERT promoter mutation, suggesting malignant transformation of PXA. The third specimen showed reduced pleomorphism, microvascular proliferation, >5 mitoses per 10 HPF, and a Ki-67 labeling index of 20% (Figure 3A and B). Immunohistochemistry was positive for GFAP and BRAF V600E (Figure 3C) and negative for CD34, IDH R132H, and H3K27M. ATRX expression was lost. Genomic profiling confirmed BRAF V600E mutation, CDKN2A/B homozygous deletion, TERT promoter mutation, PTEN alteration, and MTAP loss. These findings were consistent with WHO 2021 grade 3 PXA. High-grade astrocytoma with piloid features (HGAP) could not be entirely excluded because methylation profiling was not performed.

Figure 3

Specimens obtained at the time of the third surgery.

(A) Hematoxylin–eosin staining showed fewer pleomorphic spindle-shaped cells with microvascular proliferation, >5 mitoses/ 10 high-powered fields. (B) Ki-67 labeling index was approximately 20% at hot spots. (C) BRAFV600E was immunohistochemically positive.

Discussion

Grade 3 PXAs exhibit higher mitotic activity and reduced pleomorphism compared with grade 2 tumors.¹²^,¹³⁾ Malignant transformation from grade 2 to grade 3 PXA occurs in 6%-9% of cases. Gross total resection remains the most important prognostic factor.²⁾

TERT promoter mutation is associated with aggressive biological behavior and malignant transformation in several tumors.⁵^,¹⁴⁾ In this case, a TERT promoter mutation may lead to malignant progression, such as malignant transformation and LMD. Among 18 previously reported cases of BRAF V600E–mutant high-grade PXA treated with BRAF-targeted therapy, only three documented the status of the TERT promoter mutation in the setting of LMD (Table 1). All of these evaluated cases harbored a TERT promoter mutation. However, given the very limited number of reported cases and the absence of systematically evaluated TERT promoter status in the remaining 15 patients, it is not possible to establish a definitive association between TERT promoter mutation and LDM. Therefore, we have revised the interpretation to state that TERT promoter mutation may be associated with malignant transformation and could potentially be related to LMD in PXA. Further studies with larger patient cohorts are required to clarify this relationship.

Table 1

Demographic, Clinical, and Survival Characteristics of 18 Patients with High-Grade Pleomorphic Xanthoastrocytoma Treated with BRAF-Targeted Therapy

Age/sex	Location	MT	Ki-67 labeling index (%)	BRAF mutation	TRET promoter mutation	LMD	Spinal radiotherapy	PFS(months)	OS (months)	Response	First treatment	Targeted therapy	Subsequent therapy	Study
CR: complete response; CT: chemotherapy; GTR: gross total resection; LMD: leptomeningeal dissemination; MT: malignant transformation; NM: not mentioned; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; RT: radiotherapy; S: surgery; SD: stable disease; STR: subtotal resection
43/M	Temporal	−	NM	+	NM	−	NM	2	4	PD	STR, RT, CT	Vemurafenib	None	Chamberlain et al. (27) (2013)
35/F	Temporal	−	15.5	V600E	+	+	−	3	4.5	PR	Non-GTR, RT	Dabrafenib	None	Usubalieva et al. (28) (2015)
41/M	Temporal	+	20	V600E	NM	−		NM	NM	CR	GTR, RT	Vemurafenib	None	Lee et al. (15) (2016)
24/M	Temporal	−	NM	V600E	NM	+	+	27 and ongoing	NM	CR	GTR, RT, CT	Dabrafenib	None	Burger et al. (16) (2017)
50/M	Temporal	−	NM	V600E	NM	+	−	8 and ongoing	NM	PR	GTR, RT, CT	Dabrafenib	None	Burger et al. (16) (2017)
16/F	Parietal	−	NM	NM	NM	+	−	15	NM	PR	Non-GTR, RT, CT	Dabrafenib, trametinib	None	Amayiri et al. (17) (2018)
23/F	Temporal	−	NM	V600E	NM	+	−	3	4	CR	Non-GTR, RT, CT	Dabrafenib, trametinib	Bevacizumab	Smith-Cohn et al. (18) (2019)
19/M	Parietal	−	2	V600E	NM	−	NM	14	NM	SD	Non-GTR, RT, CT	Dabrafenib, trametinib	Chloroquine	Piña et al. (20) (2020)
16/F	Frontal	−	15	V600E	NM	+	+	5	11	PR	Non-GTR, RT, CT	Dabrafenib, trametinib	Bevacizumab	Thomas et al. (19) (2019)
14/M	Temporal	−	>90	V600E	NM	+	+	13	36	NM	S, RT, CT	Vemurafenib, trametinib	Encorafenib, binimetinib, nivolumab, ipilimumab	Kata et al. (21) (2022)
28/F	Frontal	−	NM	V600E	NM	−	NM	48	72	SD	S, RT, CT	Dabrafenib, trametinib	Encorafenib, binimetinib, nivolumab, ipilimumab, bevacizumab	Kata et al. (21) (2022)
20/M	Parieto-occipital	−	30	V600E	NM	−	NM	5	NM	PR	Non-GTR, RT, CT	Vemurafenib, cobimetinib	None	Kata et al. (21) (2022)
46/F	Medulla	−	NM	V600E	NM	+	+	6	NM	SD	S, RT, CT	Vemurafenib, cobimetinib	Encorafenib, binimetinib	Bazer et al. (22) (2024)
21/F	Frontal	−	NM	V600E	NM	−	NM	57 and ongoing	NM	CR	Non-GTR, RT, CT	Dabrafenib, trametinib	None	Castelli et al. (23) (2024)
33/F	Temporal	+	NM	V600E	NM	+	−	15	40	PR	GTR, RT, CT	Dabrafenib, trametinib	None	Inoue et al. (24) (2024)
16/M	Occipital	+	60	V600E	NM	+	−	8 and ongoing	NM	PR	GTR, RT, CT	Dabrafenib, trametinib	None	Vermeulen et al. (26) (2024)
17/M	Temporal	−	NM	V600E	+	+	+	8	NM	PR	S, RT, CT	Dabrafenib, trametinib	None	Kawaguchi et al. (25) (2024)
22/M	Temporal	+	20	V600E	+	+	+	8	NM	PR	GTR	Dabrafenib, trametinib	None	Present case

BRAF V600E mutation constitutively activates the mitogen-activated protein kinase (MAPK) pathway. Combined BRAF–MEK inhibition has demonstrated efficacy in BRAF-mutant gliomas.¹⁰^,¹¹⁾ Compared with low-grade BRAF V600E–mutant gliomas, high-grade BRAF V600E–mutant gliomas were associated with reduced median progression-free survival (PFS; 3.8 months vs. not reached).¹¹⁾

To the best of our knowledge, 18 cases of high-grade PXA treated with BRAF-targeted therapy were reported (Table 1).¹⁵^-²⁸⁾BRAF V600E mutation was identified in almost all cases (16/18); of the remaining two cases, one had no mention, and the other lacked specific mutation details. LMD was observed in 12/18 cases, and spinal irradiation was performed in six of these patients. All patients in the previous reports started BRAF-targeted therapy after dissemination of high-grade PXA, and their symptoms disappeared relatively rapidly.²⁸⁾ Median PFS was 8 months and was shorter in LMD than in no LMD (7 vs. 14 months). Median PFS was 8 months and was shorter in LMD than in no LMD (7 vs. 14 months). Among the 17 patients evaluable for radiological response, 13 (76%) achieved a radiological response (Table 1). With the exception of the four cases, all experienced recurrence during targeted therapy but lived for more than 8 months after LMD (Table 1), which remains a significant limitation of BRAF-targeted therapy.

The coexistence of BRAF V600E and TERT promoter mutations has been associated with aggressive tumor behavior and poor prognosis in several malignancies, including melanoma and thyroid carcinoma.²⁹^,³⁰⁾ Interestingly, experimental studies have suggested that this comutation may also confer enhanced sensitivity to BRAF–MEK inhibition. However, to the best of our knowledge, such a synergistic therapeutic effect has not been reported in gliomas. In our literature review, only three cases of high-grade PXA with both BRAF V600E and TERT promoter mutations were identified. The mean PFS in these cases was 6.3 months, which does not indicate a clear survival advantage compared with high-grade PXA overall. Therefore, while the coexistence of these mutations may influence tumor biology, further studies with larger patient cohorts are required to clarify their potential synergistic role in therapeutic responsiveness in gliomas.

In our patient, BRAF–MEK inhibition and spinal irradiation achieved symptomatic improvement and radiological response, although progression eventually occurred. These findings support the potential role of molecularly targeted therapy in selected cases of disseminated high-grade PXA.

Limitations

This study has a few limitations. First, the timing of the acquisition of the TERT promoter mutation could not be determined because this mutation was not assessed at the time of the initial resection. The mutation was first identified after the initial recurrence.

Second, HGAP could not be completely excluded. Methylation profiling was not performed, and the third surgical specimen showed CDKN2A/B homozygous deletion and ATRX loss, findings that may also be observed in HGAP.³¹⁾ However, the presence of a BRAF V600E mutation—more commonly associated with PXA than with HGAP, in which KIAA::BRAF fusion is frequently reported³¹^,³²⁾—together with the histopathological features of the initial specimen, supported the interpretation of malignant transformation of PXA. Based on these clinicopathological and molecular features, the tumor was considered to represent malignant transformation of PXA.

Finally, only three reported cases of high-grade PXA had documented TERT promoter mutation, and all of these cases developed LMD. Although the number of evaluated cases remains limited, this observation raises the possibility that TERT promoter mutation may be associated with aggressive tumor behavior and dissemination. Further studies with larger patient cohorts are required to clarify the relationship between TERT promoter mutation and LMD.

Conclusion

This case demonstrates that BRAF–MEK inhibition and spinal irradiation can achieve meaningful clinical and radiological improvement in BRAF V600E–mutant high-grade PXA with LMD. Although a TERT promoter mutation was identified, its association with dissemination remains uncertain due to the limited number of evaluated cases. Further studies are required to clarify this relationship.

Acknowledgments

We thank all medical staff who cared for the patient and ThinkSCIENCE (thinkscience.co.jp) for English language editing.

Conflicts of Interest

All authors have no conflict of interest.

Informed Consent

Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

References

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