Recurrent TRAF7-mutated meningioma: Molecular evolution and therapeutic insights

Abstract

Meningiomas are the most common primary intracranial tumors, with TRAF7 mutations identified in ~25% of cases. These mutations, associated with NFκB pathway activation, are linked to higher recurrence rates than other low-grade-associated mutations. We report a 49-year-old Caucasian woman with recurrent TRAF7-mutated World Health Organization Grade 2 meningiomas. Initially diagnosed with World Health Organization Grade 1 meningiomas in 2015, her disease progressed to Grade 2 chordoid meningioma by 2021. Molecular profiling revealed a TRAF7 exon 20 (p.R653Q) mutation and PMS2 deletion. Multiple surgical resections, radiation, and systemic therapies, including lanreotide, bevacizumab, and pembrolizumab, were employed, with pembrolizumab showing a favorable response due to mismatch repair deficiency. This case highlights the molecular and histological evolution of TRAF7-mutated meningiomas and the potential of immunotherapy in recurrent cases. The absence of targeted therapies for TRAF7-positive tumors underscores the need for mutation-specific clinical trials.

Introduction

Meningiomas account for approximately one-third of primary intracranial tumors, with an annual incidence of nearly 39,000 cases in the United States (2017–2021). ¹ The World Health Organization (WHO) classifies meningiomas into Grades 1 (benign, 80%–85%), 2 (atypical, 17%), and 3 (anaplastic, 2%). ² Molecular profiling has identified NF2 mutations in 40%–60% of meningiomas, predominantly in aggressive subtypes, while TRAF7 mutations, present in 20%–25% of cases, are mutually exclusive with NF2 and more common in Grade 1 tumors. ³

TRAF7 mutations, located on chromosome 16p13.3, activate the NFκB pathway, promoting cell survival and growth. ³ Although historically associated with lower recurrence risk, recent studies report a 14.7% recurrence rate at 2 years for TRAF7-mutated meningiomas, compared to single recurrences in mutations of transcription factors such as Kruppel-like factor 4 and tumor suppressors such as SMARCB1. ⁴ TRAF7 mutations often co-occur with phosphoinositide 3-kinase pathway or KLF4^K409Q mutations, influencing tumor behavior.^3,4 Despite their prevalence, no standardized systemic therapies exist for TRAF7-mutated meningiomas, highlighting a critical research gap.

Case presentation

A 49-year-old Caucasian woman presented in 2014 with right-sided pulsatile tinnitus and conductive hearing loss following a fall. Physical exam showed the right external auditory canal was narrowed by soft tissue, and the tympanic membrane had reduced mobility. Impedance audiometry testing showed a type B pattern with normal ear canal volume in the right ear, indicating conductive hearing loss in that ear. The left ear showed a type A tympanogram with hearing within normal limits. A computed tomography (CT) identified fibrous dysplasia of the right temporal bone, but a 2015 mastoidectomy revealed a WHO Grade 1 meningioma (Table 1). Brain magnetic resonance imaging (MRI) confirmed multiple intracranial meningiomas, and next-generation sequencing was negative for NF2 mutations, with a variant of BARD1, a tumor suppressor gene, of uncertain significance identified on germline testing.

Table 1.

Surgical resection of meningiomas, date, pathology grade, and genomic alterations.

Surgery date	Type of surgery	Grade	NGS
July 08, 2015	Right mastoidectomy and canalplasty with excision of benign lesion	Grade 1 meningioma	Insufficient tumor quant
February 21, 2018	Transsphenoidal resection of a tuberculum sella meningioma with reconstruction of the anterior skull base using vascularized nasal septal flap	Grade 1 meningioma
March 04, 2019	Left craniotomy for partial resection of the meningiomas on the greater wing of the left sphenoid and on the involved bone in the anterior middle cranial fossa	Grade 1 meningioma	Insufficient tumor quantity for Caris
December 03, 2019	A subtotal resection of the transosseous meningioma in the right middle cranial fossa	Grade 1 meningioma	Insufficient tumor quantity for Caris
November 30, 2021	A combined parietal craniotomy with suboccipital retromastoid craniotomy for resection of a left posterior fossa infratentorial, supratentorial meningioma with extension along the tentorium, transverse sinus, sigmoid sinus, and parietal cortex	Grade 2 chordoid meningioma	PMSD deletionTRAF7 positivePositive MSH-2, MSH-6, MLH-1

NGS: next-generation sequencing.

By 2017, a tuberculum sellae meningioma caused optic nerve displacement, prompting resection (Grade 1) in 2018 (Table 1). In 2018, blurry vision in the left eye led to the discovery of dural-based masses at the left sphenoid bone. Ocular examination revealed an afferent pupillary defect and a loss of visual acuity in the left eye. Extraocular movements were also reduced in the left eye. The right eye had normal vision and extraocular movements on ocular examination. A 2019 craniotomy partially resected these lesions. Pathology revealed fascicles of syncytial cells and eosinophilic cytoplasm with some extracellular matrix but no obvious chordoid or clear cell features and no mitotic figures consistent with a Grade 1 meningothelial meningioma (Table 1 and Figure 1(a)–(f)). By late 2019, right-sided ear pain prompted resection of a right middle cranial fossa meningothelial meningioma with transosseous extension (Table 1). The specimen under the microscope revealed no mitotic figures and fascicles of syncytial cells consistent with the diagnosis (Figure 1(g)–(i)).

Figure 1.

Histopathological images of meningiomas. (a–c) H&E, 5×, 20×, 4×, left temporal bone (March 04, 2019). (d–f) H&E, 5×, 20×, 40×, left orbital skull (March 04, 2019). (g–i) H&E, 5×, 20×, 40×, temporal meningioma (December 03, 2019). (j–l) H&E, 5×, 20×, 40×, left tentorial meningioma (November 30, 2021).

In 2020, a Ga-68 DOTATATE positron emission tomography–CT revealed significant tracer uptake indicative of multiple intracranial meningiomas, predominantly in the left temporal lobe extending from the tentorium to the sigmoid and left straight sinuses, and the roof of the left temporal bone, and lanreotide (120 mg every 28 days) was initiated (Figure 2(a)). However, in early 2021, progressive left-sided vision loss prompted a brain MRI showing an unchanged left orbital meningioma (Figure 2(b)). These symptoms led to resection of the left cavernous sinus mass, which was diagnosed as a WHO Grade 2 chordoid meningioma. Bevacizumab (15 mg/kg every 3 weeks) was started but discontinued due to wound dehiscence. A 2021 craniotomy was done for a growing left cavernous sinus meningioma (8.5 mm; Figure 2(c)). Microscopic examination of the specimen showed a meningothelial neoplasm with fascicles of syncytial cells and, in areas, myxoid extracellular matrix, consistent with a Grade 2 chordoid meningioma (Figure 1(j)–(l)). Molecular profiling revealed a TRAF7 (p.R653Q) mutation and deletion of PMS2, which encodes a protein involved in mismatch repair (MMR) of DNA (Table 1). Radiation therapy (54.6 Gy) was administered. It was followed by three rounds of pembrolizumab (200 mg every 3 weeks), targeting MMR deficiency and considering potential programmed death-ligand-1 (PD-L1) expression influenced by tumor grade and tumor microenvironmentfactors, such as IFN-γ, which may be indirectly associated with TRAF7 signaling, leading to clinical improvement. After the three rounds of pembrolizumab, imaging showed no change in the size of the multiple intracranial meningiomas of the left sphenoid wing within the left orbital apex. Over the next couple of months, the patient reported no worsening of symptoms or new neurological deficits after the pembrolizumab infusions. Imaging has continued to show no increase in size or progression of meningiomas of the left sphenoid wing within the left orbital apex (Figure 2(d)).

Figure 2.

Imaging studies. (a) Ga-68 DOTATATE PET–CT, axial, 2020. (b) MRI brain T1 RAGE axial with gadolinium, 2021. (c) MRI orbit T1 axial TSE FS with gadolinium, 2021. (d) MRI brain T1 coronal RAGE 3D non-IR, 2025.

Discussion

Meningiomas pose therapeutic challenges due to high recurrence rates, with 10-year survival rates of 83.7%, 53%, and 0% for Grades 1, 2, and 3, respectively. ³ Surgery and radiation remain primary treatments, ⁵ but no preferred systemic therapy exists for recurrent high-grade meningiomas.^6,7 TRAF7-mutated meningiomas, despite their prevalence, lack targeted therapies.

Somatostatin analogs, such as lanreotide, target somatostatin receptor 2A but have shown limited efficacy, as seen in our patient and a phase II trial where all patients progressed within 10 months. ⁸ Bevacizumab, a vascular endothelial growth factor inhibitor, stabilized our patient’s disease temporarily, with studies reporting 44% progression-free survival at 6 months.^9,10 Pembrolizumab, a PD-L1 receptor blocker, showed promise in our case, supported by reports of efficacy in MMR-deficient meningiomas.^11,12 Our patient had symptomatic improvement after her infusions of pembrolizumab. The patient had complained of worsening vision in her left eye, which became stable after pembrolizumab infusions. Patient also had a history of seizures due to her multiple intracranial meningiomas that occurred previously to and during radiation therapy. After pembrolizumab therapy, her seizures stopped. However, a phase II trial of nivolumab showed no survival benefit in Grade 2 meningiomas, emphasizing the need for mutation-specific studies.^13,14

The molecular evolution from Grades 1 to 2 in our patient underscores the dynamic nature of TRAF7-mutated meningiomas. Future research must prioritize targeted therapies and clinical trials for TRAF7-positive tumors to address this unmet need.

Conclusion

This case highlights the molecular and histological evolution of TRAF7-mutated meningiomas and the potential of immunotherapy in recurrent cases. The absence of targeted therapies for TRAF7-positive tumors underscores the need for mutation-specific clinical trials.