Multiple meningiomas arising within the same hemisphere associated with Li-Fraumeni syndrome.

BACKGROUND: While meningiomas are some of the most common intracranial tumors, the presence of multiple ones at the time of presentation is rare and can most commonly be observed in patients with well-described syndromes (i.e., neurofibromatosis type 2) or those with prior cranial radiation history. In others, however, the pathophysiology remains unclear. CASE DESCRIPTION: A 49-year-old female with no significant personal or familial oncologic medical history presented with a generalized seizure and was found to have ten meningiomas arising within the right hemisphere. She underwent a two-staged resection of all tumors, with pathology revealing the World Health Organization Grade I meningioma. Whole-exome sequencing revealed somatic NF2 mutations and heterozygous deletion of chromosome 22 overlapping with NF2, and analysis of the germline uncovered mutations of TP53, rendering a diagnosis of Li-Fraumeni Syndrome.
CONCLUSIONS: This case represents a novel presentation of multiple meningiomas in a patient with newly diagnosed Li-Fraumeni syndrome, suggesting meningioma may be considered as part of this tumor-predisposed patient population. Copyright:

INTRODUCTION

While meningioma is one of the most common types of intracranial tumor, the presence of multiple meningiomas occurs in approximately 10% of these patients at the time of diagnosis.[24] In a majority of these cases, patients have a prior history of cranial irradiation or are genetically predisposed with an underlying syndrome such as neurofibromatosis type 2.[25] Indeed these tumors may have a propensity to behave more aggressively than typical World Health Organization (WHO) Grade I meningiomas with higher rates of radiographic recurrence.[12,24] While the genetic landscape of sporadic meningiomas has been elucidated in recent years,[4] the pathogenesis of multiple meningioma formation is not well understood.

CASE DESCRIPTION

A 49-year-old female presented with a new-onset generalized seizure and was found to have multiple hyperdense masses with calcifications in the right hemisphere on computed tomography. A brain magnetic resonance imaging with and without contrast demonstrated ten distinct dural-based, homogeneously enhancing lesions within the right hemisphere (Figure 1a-c), the largest measuring 5 × 8 cm (arrow, Figure 1c) and effacing the lateral ventricles. On examination, she was neurologically intact. Her medical history was significant for basal cell carcinoma of the face excised four years earlier. Family history was unremarkable.

Figure 1:

Magnetic resonance imaging of multiple meningiomas arising within the same hemisphere. (a-c) Representative axial slices of T1-weighted magnetic resonance images after gadolinium contrast administration are shown. The arrows point to the (b) smaller frontal convexity tumor (c) and dominant parafalcine tumor, targeted through surgical resection.

She was taken to the operating room for resection of the dominant right parafalcine mass (arrow, Figure 1c) and four other (arrow, Figure 1b) lesions that were amenable to the same incision and craniotomy access. Although the tumors all displayed a mildly elevated Ki-67 index of 5–10% on histologic examination, they did not meet criteria for an atypical meningioma diagnosis and thus the final diagnosis was the WHO Grade I meningioma. Whole exome sequencing (WES) of the resected tumors and matching blood was performed and identified the presence of the same clonal somatic NF2 nonsense mutation and somatic heterozygous deletion of chromosome 22 overlapping with NF2. Germline mutations in NF2 were not found. However, a germline missense mutation in TP53 (c.542G >A, p.Arg181His) was revealed, previously described as deleterious.[7] Subsequently, the patient was referred for formal genetic testing, which confirmed this finding, and she was diagnosed with Li-Fraumeni syndrome. Postoperatively, the patient underwent periodic surveillance imaging to monitor for growth of her tumors. Twenty-eight months after surgery, she underwent the second stage of resection of the progressively enlarging, although asymptomatic tumors that remained, which similarly demonstrated WHO Grade I pathology and a mildly elevated Ki-67 index of 4–6%.

WES of all tumors revealed the same somatic NF2 nonsense mutation and chromosome 22 deletions with otherwise normal copy numbers of all other chromosomes. Additional somatic mutations unique to each sample were discovered, but likely non-pathogenic as none were previously characterized as oncogenic [Supplementary Table]. Together, these findings suggested that all tumors originated from the same founding clone.

DISCUSSION

The differential diagnosis for multiple dural-based lesions includes meningioma and metastasis, but the appearance and lack of vasogenic edema typically favors the former. Among the approximate 10% of meningioma patients harboring multiple tumors at the time of diagnosis,[15,17] a subset exhibit known risk factors, such as a history of prior cranial irradiation or an underlying diagnosis of genetic syndromes such as Neurofibromatosis 2 or Cowden Syndrome.[22,24] However, in most instances, multiple meningiomas arise sporadically and are typically driven by somatic mutations of NF2, followed by a second-hit characterized by loss of chromosome 22.[4,21,23] Interestingly, multiple meningiomas in patients without previous risk factors may anecdotally occur on just one side in some patients.[18] While multiple meningiomas have not been previously described in the setting of Li-Fraumeni syndrome, a single case of a patient with a solitary benign meningioma in the context of a medical history of numerous other malignancies has been reported.[6] Aside from the history of a basal cell carcinoma, the patient presented had no other significant relevant history, making her presentation of multiple meningiomas in the setting of newly-diagnosed Li-Fraumeni syndrome previously undescribed.

The pathogenesis of multiple meningioma formation remains poorly understood. Early theories hypothesized spread of original clonal tumor cells through the cerebrospinal fluid.[14,26] However, this has not garnered support as cerebrospinal fluid dissemination is infrequent and rarely seen in cases of aggressively behaving sarcoma-like meningiomas often with extracranial metastasis.[3] A more plausible explanation relates to an inherent multicentricity of tumor foci, perhaps secondary to intrinsic genetic changes in the dura itself, leading to tumor growth under the influence of local oncogenic factors.[2,13] This could indeed offer insight into the reports of multiple tumors confined to one hemisphere.

In the patient presented, the relevance of the germline TP53 mutations remains unclear. While TP53 mutations have been frequently described in other brain tumors, such as gliomas, there have been more limited reports in meningioma. They have typically been reported in higher grade meningiomas[16,19] but have also been found in the WHO Grade I tumors as, similar to this patient.[1,20] However, unlike the TP53 mutation in the presented patient, which had a known association with Li-Fraumeni syndrome, less than half of the reported mutations were predicted to be deleterious, and correlations with clinical outcomes remain unclear. The somatic NF2 mutation detected in this patient’s tumors, on the other hand, along with the heterozygous deletion of chromosome 22 overlapping with NF2, likely represents the major driver mutation leading to meningioma formation in this case based on recent discoveries of mutually exclusive meningioma genomic subgroups.[4,5,9] Clinically, NF2 mutated meningiomas can be associated with more aggressive features, such as atypical (i.e., WHO Grade II) histology, as well as others, leading to more malignant behavior and higher rates of recurrence.[25] While the pathogenic contribution of the germline TP53 mutations found in the current patient remains unclear, particularly in regard to the development of multiple tumors with the more aggressive NF2 mutated subgroup, multiple meningiomas remains a novel clinical presentation of Li-Fraumeni syndrome.

Management of multiple meningiomas, such as solitary tumors, remains maximal surgical resection when tumors become symptomatic or reach significant size with associated mass effect. While there is currently no effective chemotherapy for meningiomas, adjuvant radiotherapy can often times be used in patients with multiple meningiomas, particularly for residual tumors or those with growing tumors that may pose a high surgical risk due to wound considerations.[8,24] In addition, it is frequently used postoperatively for higher grades (i.e., WHO Grade II or III) tumors. In this particular case, however, the discovery of LiFraumeni syndrome precluded the potential use of radiation, given the well-established increased risk for development of further radiation-induced malignancies in these patients.[10,11] Thus, the presented patient continues to undergo periodic surveillance imaging of her tumors with the understanding that additional surgery will likely be necessary as the only effective and safe modality to control her disease.

CONCLUSION

Although the role of germline TP53 mutations in the formation of multiple meningiomas remains unclear, this case is a novel presentation of multiple meningiomas in a patient with newly-diagnosed Li-Fraumeni syndrome, in the absence of more common predisposing risk factors. Multiple meningiomas may be considered as part of the spectrum of tumors that can develop in patients with Li-Fraumeni syndrome and given its implications in the overall treatment, seemingly important to recognize and consider.

Supplementary Table 1:

Whole-exome sequencing data of tumor samples from both surgeries of index patient.