Glioblastoma in a Patient with Neurofibromatosis Type 1: A Case Report and Literature Review

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited affection characterized by a higher chance of development of tumors. There have been only few cases of glioblastoma (GBM) in adult NF1 patients. In this paper, we present the case of 43 years old patient who presented initially amnesia and seizures. The patient underwent gross total surgical excision, followed by the Stupp protocol. He received concomitant chemo-radiotherapy with temozolomide then adjuvant temozolomide chemotherapy. We have also reviewed the literature and reported the cases of GBM in NF1 patients previously published.


Introduction
Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary familial disease that affects multiple organ systems with a wide range of clinical manifestations and varying rates of progression and severity of complications.The prevalence of neurofibromatosis type 1 is approximately 1 case per 3,000 individuals [1].There are two other conditions described under the term "neurofibromatosis": neurofibromatosis type 2 and schwannomatosis.They are clinically and genetically distinct from neurofibromatosis type 1.Several studies have examined the relationship between gene function at the cellular level and various clinical manifestations, including the development of neoplasms.Among these neoplasms, malignant tumors of the neuroectoderm, such as malignant schwannoma and gliomas, are common in adults.While children with NF1 frequently develop tumors such as rhabdomyosarcoma, leukemia, and optic gliomas [2].Several studies have reported glioblastomas in patients with NF1.In this study, we report the case of glioblastoma in adult patient with NF1, its clinical, radiological and pathological characteristics, as well as its treatment and follow-up.

Clinical Case
We report the case of a 43-year-old patient, who had a family history of NF1.His mother, two sisters and daughter were also affected by NF1.He was in good general condition, without toxic habits and without health problems.The patient had multiple café-au-lait spots all over his body and a soft cutaneous mass of 3 cm in the epigastric region (Fig. 1).The patient suddenly developed amnesia and a few hours later generalized convulsive seizures, without fever or other symptoms.On initial clinical examination, the patient was conscious, with normal vital signs, without meningeal syndrome or neurological deficit.Numerous investigations were carried out.
Brain MRI showed bilateral hippocampal lesions of high signal intensity on T1-and T2-weighted images, without enhancement.Magnetic resonance spectroscopy showed a decrease in NAA peak and a moderate choline peak.The diagnosis of an autoimmune and paraneoplastic limbic encephalitis was initially suspected.Biochemical analysis of cerebrospinal fluid showed moderate hyperproteinorachia.The search for onconeural antibodies was negative.Thoracic, abdominal, and pelvic CT scans showed no abnormalities.Viral serologies were also negative.A new MRI was performed two months later and revealed bilateral hippocampal lesions and the appearance of a new lesion occupying the space in the left posterior temporal lobe, measuring 67 × 61 × 48 mm, with low signal intensity on T1-weighted sequence and high signal intensity on T2 sequence, with minimal enhancement (Fig. 2).The Swan sequence revealed moderate intraluminal vascularization within the new temporal lesion.While spectroscopy showed a choline peak without a lipid peak.After discussion in a multidisciplinary consultation meeting, the patient underwent a stereotactic biopsy of the left posterior temporal lesion.The histopathological analysis revealed a diffuse infiltrating tumor proliferation of glial nature.The cell density was high.The cells were often globular and sometimes rounded.The nuclei were atypical and irregular (Fig. 3).Immunohistochemical studies showed expression of GFAP (Fig. 4).ATRX expression was conserved.P53 was also expressed while IDH1 was not expressed by the tumor cells (Fig. 5).The diagnosis of a wild-type IDH glioblastoma was established.A third brain MRI was performed and showed an increase in the volume of the temporo-parietal intra-axial lesion occupying the space and a stable aspect of the bilateral hippocampal lesions.The patient underwent subtotal resection of the temporo-parietal lesion.The diagnosis of wild-type IDH glioblastoma was confirmed.The patient then received adjuvant treatment according to the Stupp protocol.Initially, he underwent external beam radiation therapy with intensity modulation in arc therapy (VMAT) at a dose of 60 Gy with a fractionation of 2 Gy per tion associated with concomitant Temozolomide-based chemotherapy at a dose of 75 mg/m 2 .After the end of concomitant radiochemotherapy, he received Temozolomide at a dose of 200 mg/m 2 /day for 5 days every 28 days for 6 months.The treatment was well tolerated overall.Throughout the treatment, the patient received supportive care.Follow-up was conducted 3 months after the end of treatment.An MRI was performed three months after the end of the treatment and showed a stable aspect of the glioblastoma measuring 65 × 62 × 27 mm, and a stable aspect of the two hippocampal lesions.The patient did not suffer from headaches or any neurological signs.
Five months after the completing of the treatment, the patient presented a bad general condition with the apparition of headaches and neurological deficit.An MRI was performed and revealed a 20% progression of the size of the lesion, measuring 78 × 73 × 53 mm with subfactorial and trans tentorial herniation.Due to the bad general condition, the patient only received palliative care.

Discussion
The main feature of NF1 is the development of neurofibromas, a nerve sheath tumor that forms in peripheral nerves.Pigmentary abnormalities (café-au-lait spots) and skeletal dysplasias are other characteristics that can be observed.
Neurofibromatosis is caused by mutations of the NF1 gene (NF1) located on chromosome 17q11.2.This gene is a tumor suppressor gene involved in RAS-MAPK (mitogenactivated protein kinase) signaling.The protein encoded by NF1 gene is neurofibromin.The later regulates cell growth and survival through several downstream signaling effectors [3].Thus, individuals affected with Neurofibromatosis   are considered to have a higher risk for development of malignancies [4], such as malignant peripheral nerve tumors (MPNST) and leukemias [5].
Besides, NF1 patients have an increased risk of developing central nervous system malignancies such as optic pathway gliomas, astrocytomas with a 5-fold increased incidence of high-grade astrocytoma.The relative risk of brain tumor in NF1 patients older than 10 years is estimated to be 100 times higher than for patients without NF1 [6].In adult NF1 patients, glioblastomas involving most of the time the cerebral hemispheres are observed [9].
In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal subtype and confers the aggressiveness of the tumor.
It is acknowledged that the mean age of patients with NF1 with glioblastoma at diagnosis is much younger (mean age 34 years) than that of patients with sporadic glioblastoma (mean age 55 to 60 years) [32].Our patient was 43 years old.Regarding the localization, GBMs that are located in the infratentorial area account for a smaller percentage than supratentorial GBMs [31], with only one case of a Cerebellopontine Angle GBM [27].
In the last couple of years, molecular features in diagnosis have gained more interest.According to the most recent edition of the WHO classification published in 2021, GBM is by definition IDH wild type [32].Molecular analysis of glioblastomas arising in NF1 patients showed the presence of genetic alterations such as p16INK4A/ARF deletion and p53 mutations [6].
As mentioned before, The NF1 mutation leads to loss of neurofibromin and a consequent increase in RAS activity.Hence, combination therapies targeting multiple steps of the RAS signaling pathway were studied to treat gliomas occurring in NF1 patients, such as mitogen-activated protein kinase (MEK) inhibitors, BRAF inhibitors, and checkpoint inhibitors.A case reported in 2020 of a IDH1 mutant glioma (considered at that time a glioblastoma) received a MEK inhibitor (trametinib 2 mg once daily) followed by a BRAF inhibitor (dabrafenib 50 mg twice daily) and was alive with complete response at 4-year follow-up [30].
Huttner et al. [34] reviewed five glioblastoma patients in children with NF1 and reported their clinicopathologic features.This study suggested that a worse overall outcome is linked to pathological hallmarks including increased p53 expression, increased EGFR amplification, and increased proliferative indices.This study also suggested that in the pediatric population NF1 patients have a better prognosis than children without NF1.
In our study, the patient was treated using surgical excision and chemoradiotherapy with temozolomide, with adjuvant temozolomide.Most of the reported cases underwent the same treatment, considering that the Stupp protocol is the standard of care.
Glioblastoma is an incurable disease with a median survival of only 15 months in cases not related to NF1, in spite of the development of treatment modalities [35].Only very few patients survive over 2.5 years, with 10 years being the longest survival that has been reported [29].

Conclusion
The management of glioblastoma in NF1 patients presents unique challenges due to the genetic background and predisposition to malignancies.Molecular features, age at diagnosis, and tumor localization should be taken into account when planning treatment strategies.While the Stupp protocol remains the standard of care for glioblastoma patients, targeted therapies addressing the specific molecular alterations and signaling pathways may offer additional benefits to NF1 patients.Further studies and clinical trials are needed to optimize treatment and improve the prognosis for patients with glioblastoma and NF1.

Glioblastoma in a
Patient with Neurofibromatosis Type 1: A Case Report and Literature Review et al.

Fig. 1 .
Fig. 1.Café-au-lait spots with a soft cutaneous mass in the epigastric region of the trunk.
Glioblastoma in a Patient with Neurofibromatosis Type 1: A Case Report and Literature Review et al.

TABLE I :
Summary of Published Cases of Adult NF1 Patients with Glioblastoma Note: SR: Surgery; RT: Radiotherapy; CT: Chemotherapy.