Yuxin Qiu1，a Daqing Sun2,b Jianwen Li2,c Furong Hao2，d*
1 School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, China
2 Department of Radiation Oncology, Weifang People’s Hospital, Weifang 261041 ,China
*Corresponding Author：wfmuqyx@126.com
Funding
This work was supported by Shandong Medical Association Clinical Research Fund (Grant No. YXH2022ZX02208).
[Abstract] Malignant Peripheral Nerve Sheath Tumor (MPNST) is a spindle cell sarcoma originating from the peripheral nerve stem, which mainly occurs in the trunk of the extremities. Primary intracranial tumors are rare. This paper reports a case of intracranial MPNST, and analyzes its clinical manifestations, imaging, pathological diagnosis and treatment, hoping to provide some reference for clinical diagnosis and treatment.
[Key words] Intracranial malignant peripheral nerve sheath tumor；Neurofibromatosis type 1 (NF1); Surgery combined with radiotherapy; Targeted therapy
Malignant peripheral nerve sheath tumor (MPNST) is a spindle cell sarcoma that originates from the peripheral nerve trunk. The proximal limbs and trunk are the main regions where MPNST occurs, accounting for more than 70%[1, 2]. Followed by the head and neck region, which accounts for approximately 10-20%. The occurrence of MPNST primarily in the intracranial region is even rarer, and the proportion in the spinal region is relatively low, less than 10% [3]. This article analyzes the clinical and pathological data of one case of intracranial MPNST occurring primarily in the intracranial region, and reviews relevant literatures for summarization, aiming to enhance the understanding of this disease.
- Case Report
- Basic Information of the Patient
The patient is a 43-year-old female who was admitted to the hospital due to “sudden limb convulsions for 26 days and speech impairment for 8 days”. An MR examination was conducted in an external hospital, which showed a huge space-occupying lesion in the left fronto-temporal region. As no treatment was carried out there, she came to our hospital for medical consultation. She has a history of congenital developmental disorder, with a malformation on the left side of her face and short stature. Her height is 140 cm and her weight is 40 kg. During the physical examination, it was found that there were “café-au-lait” spots on the patient’s whole body skin, and there were soft exophytic papules and polypoid protrusions of varying sizes all over the body, which were occasionally pedunculated, especially prominent on the trunk and rare on the tongue (as shown in Figure 1 and Figure 2). The patient has a protruding left eye and ptosis of the left eyelid, while there is no abnormality in the right eye.
Examination: The patient is conscious but in poor spirit, with a GCS score of 12 points; her speech is slurred, and the Kubota Drinking Water Test result is Grade 1; for the head, a skull defect can be felt in part of the left side of the skull; for the cranial nerves, there is no abnormality in the I and II cranial nerves. For the III, IV, and VI cranial nerves, there is incomplete ptosis of the left eyelid, protrusion of the left eyeball, no abnormalities in the right eye, a decreased accommodation reaction of the left eye, and partial limitation of the movement of the left eye. For the V cranial nerve, there is a decrease in the superficial sensation on the left side and weakness of the left temporalis muscle, and there is no abnormality in the remaining cranial nerves. Moreover, both the patient’s elder sister and daughter have “café-au-lait” spots on their skin.
Figure 1: The skin manifestations on the patient’s trunk.
Figure 2: Verrucous protrusions can be seen on the surface of the patient’s tongue
- Main Symptoms
The patient had an epileptic seizure on December 4, 2024, which lasted for 20 minutes. Then, on December 23, 2024, she developed speech impairment, memory loss, accompanied by headache. There was no nausea, vomiting, facial numbness, or incontinence of urine and feces.
- Treatment
On January 10, 2025, the patient underwent “Temporal lobe lesion resection; Frontal lobe lesion resection + Skull lesion resection + Titanium mesh implantation + Dural patch repair” under general anesthesia in the Department of Neurosurgery of our hospital. During the operation, it was observed that part of the dura mater was eroded by the tumor. There was no obvious boundary between the tumor and the surrounding brain tissue, and the branches of the middle cerebral artery were involved in supplying blood to the tumor. The postoperative pathological examination indicated a low-grade malignant peripheral nerve sheath tumor, WHO Grade 2. Therefore, on February 13, 2025, the patient started postoperative adjuvant radiotherapy with a dose of: PTV: 50Gy/25 fractions. Currently, she is still undergoing radiotherapy.
- Postoperative Condition
The surgical wound healed well. The patient developed hypostatic pneumonia and lower limb venous thrombosis, which improved after symptomatic treatment. Since the operation, the patient has been taking levetiracetam orally for antiepileptic treatment. Later, due to the high cost, it was changed to sodium valproate tablets. There has been no recurrence of epileptic seizures since the operation.
- Auxiliary Examinations
- Imaging Examinations
The main abnormalities found in the patient’s MRI of the cranium, neck, thorax, and lumbosacral spine were as follows: The sagittal STIR sequence showed a scoliotic deformity of the thoracic spine, with T4 and T5 presenting as hemivertebrae deformity. The spine was significantly curved to the left. The 2D-MRM indicated a significant lateral curvature of the subarachnoid space at the thoracic spine level, and no obvious abnormal enhanced lesions were observed after enhancement. After injection of GD-DTPA, axial, sagittal, and coronal T1WI scans showed that there was a huge irregular heterogeneous signal from the left temporal lobe to the frontal lobe and orbit. There was an oval lesion about 46mm×42mm, surrounded by an edema zone. The T2FLAIR sequence showed partial diffusion restriction. The adjacent bone plate became thinner and there were partial defect changes. After enhancement, the lesion showed uneven and relatively obvious enhancement. Part of the left meninges was enhanced, and multiple enhanced nodular lesions were seen in the scalp soft tissues. The left brain was compressed, the ventricular system was compressed and narrowed, and the midline structure shifted to the right. The conical structure of the left eye was compressed and displaced, and the left eyeball protruded. No other obvious abnormalities were found. As shown in Figure 3.
Figures 3a and 3b: Axial and coronal views after T1 enhancement respectively. A huge irregular heterogeneous signal can be seen extending from the left temporal lobe to the frontal lobe and orbit, surrounded by an edema zone, and it invades the cranial bone.
Figure 3c: T2 fat suppression; Figure 3d: Axial view of T2 FLAIR. The sequence shows partial diffusion restriction. The adjacent bone plate becomes thinner and there are partial defect changes. After enhancement, the lesion shows uneven and relatively obvious enhancement. The left brain is compressed, the ventricular system is compressed and narrowed, and the midline structure shifts to the right.
- Postoperative Pathology
Gross Pathology: One piece of grayish-white irregular tissue, with a volume of 6.5cm×4cm×2.5cm. The cut surface is grayish-white and grayish-yellow, and the texture is soft. For the cytopathology (as shown in Figure 4), most of the cells are spindle-shaped, asymmetric and long spindle-shaped. The nuclei are darkly stained, wavy or comma-shaped, arranged in bundles or palisades. Epithelioid cells account for a small proportion, which are characterized by large cells, abundant cytoplasm, round or oval nuclei, similar to the differentiation of carcinoma, melanoma or rhabdomyoblasts. Pathological diagnosis: (Tumor in the left fronto-temporal region) Neurogenic tumor. The cell density is increased, focal necrosis can be seen, and the mitotic count is approximately 6 per 10 high-power fields (HPF). Combined with the immunohistochemical results and the opinions of remote expert consultations, it is consistent with a low-grade malignant peripheral nerve sheath tumor.
Immunohistochemical Results: Vimentin (+), S-100 (+), SOX10 (+), GFAP (+), EMA (-), PR (-), SSTR-2 (-), Ki-67 (index 8%), CD34 (positive in blood vessels).
Figure 4: Pathological images of a patient with intracranial malignant peripheral nerve sheath tumor (HE staining)
The left image is under a low-power microscope field (×10), and the right image is under a high-power microscope field (×20)
- Discussion
- Epidemiology
Malignant peripheral nerve sheath tumor is a rare malignant soft tissue sarcoma, accounting for 5%-10% of all soft tissue sarcomas. The annual incidence rate is approximately 0.001 per 100,000 people. Moreover, it is associated with neurofibromatosis type 1 (NF1)[4, 5], The lifetime risk of MPNST in patients with NF1 is 8%-13%[4, 6], which is significantly higher than that in the general population. MPNST is more prevalent among young and middle-aged people, mostly between the ages of 20 and 50. Its occurrence in children is rare, and there are more male patients than female patients, with a male-to-female ratio of approximately 1.5:1[6]. MPNST has a predilection for the limbs, especially the sciatic nerve, brachial plexus nerve, trunk, head and neck regions. Approximately 10% of cases occur in the intracranial region or paravertebral area[7, 8].
- Pathogenic Factors
The main risk factor for the development of MPNST is the NF1 gene mutation. Approximately 50% of the cases are associated with NF1, and the prognosis of such patients is often worse[9]. In addition, patients with a history of radiotherapy have an increased risk of developing MPNST. Extremely rarely, some benign neurofibromas may progress into MNPST. Moreover, the deletion of H3K27me3 caused by the SUZ12/EED mutation is also a factor contributing to the occurrence of MPNST. This gene mutation often indicates a dysregulation of epigenetic control[10]. Additionally, some researchers have found that certain genomic instabilities, such as mutations in genes of TP53, CDKN2A/B, and the PRC2 complex[11], can also lead to the development of this disease.
- Diagnosis
The diagnosis of MPNST mainly relies on pathology. Its immunohistochemical findings are consistent with the typical manifestations of schwannoma. Specifically, it shows S-100 (+), SOX10 (+), and EMA (-). The loss of p16/CDKN2A expression, an increased Ki67 labeling index, and extensive nuclear p53 positivity are also characteristic features of MPNST[10].
- Treatment
- Traditional Treatment
Currently, the treatment of MPNST mainly consists of surgical resection supplemented by postoperative radiotherapy[5]. Surgical resection is the only method that may cure the disease. However, it is necessary to ensure that the surgical margin is negative with a width of ≥1 cm to reduce local recurrence. Nevertheless, the difficulty of surgery varies depending on the location of the tumor. Some tumors often invade nerve plexuses or major blood vessels, making it difficult to preserve functions[12]. Postoperative adjuvant radiotherapy is an effective means of reducing the local recurrence rate[13]. Relevant studies have shown that proton or carbon ion radiotherapy has more dosimetric advantages for paravertebral tumors. Chemotherapy is currently less commonly used in clinical practice. The main first-line chemotherapy regimen is doxorubicin combined with ifosfamide, but the objective response rate (ORR) is only 20%-30%[14].
- Targeted Therapy
Regarding mitogen-activated protein kinase kinase (MEK) inhibitors, HIRBE has introduced the relevant role of selumetinib in the treatment of NF1-related MPNST. Its main mechanism of action is that the deficiency of NF1 leads to the activation of the RAS-MAPK pathway[13]. In addition, PARP inhibitors can take advantage of the genomic instability of MPNST, such as homologous recombination deficiency, to inhibit the proliferation of tumor cells. Moreover, considering that a large number of MPNST patients have CDK4 amplification as a target, palbociclib used alone or in combination with MEK inhibitors has also been included in the research[15, 16].
- Immunotherapy
Currently, the main immunotherapy involves PD-1/PD-L1 inhibitors, and the combination of radiotherapy and PD-1 inhibitors can enhance the immune response. For example, pembrolizumab[4]. In addition, some studies have shown that tumor-infiltrating lymphocytes (TIL) are effective against metastatic MPNST, with an objective response rate (ORR) of approximately 25%[17, 18].
- Other Therapeutic Researches
In addition, there are some emerging studies that guide the treatment of MPNST. For example, tumors can be classified into “inflammatory type”, “proliferative type” and “mesenchymal type” based on the gene expression profile, so as to guide the selection of targeted drugs. HDAC inhibitors such as vorinostat can inhibit tumor growth by regulating chromatin remodeling[19]. For the deficiency of H3K27me3, E2H2 inhibitors can be used for treatment[9]. Nanomedicines like liposomal doxorubicin can increase the local drug concentration in tumors[20], reduce systemic toxicity, and thus alleviate the side effects of chemotherapy on patients.
- Challenges and Prospects
Currently, the main challenge in the treatment of intracranial MPNST is the insufficient surgical margin. Since the tumor often invades nerve plexuses or major blood vessels, it is difficult to achieve R0 resection, especially for tumors located in the spine and skull base areas[21]. In addition, the radiotherapy sensitivity of MPNST is lower than that of other sarcomas, and the response rate of the traditional chemotherapy regimen (doxorubicin + ifosfamide) is also relatively low, only 20-30%[9]. Moreover, there is a lack of biomarkers that can predict its curative effect. Considering the genetic complexity of MPNST, such as the coexistence of NF1 deficiency, CDKN2A inactivation, and PRC2 complex mutations (such as EED/SUZ12), it is likely to lead to the failure of single-targeted therapy. Furthermore, due to the diversity of its molecular subtypes, individualized treatment also needs to be emphasized. In addition, the immune microenvironment of this tumor will also affect the treatment effect. MPNST has the characteristics of a “cold tumor”, specifically manifested by a small number of T cell infiltrations and low PD-L1 expression. The effective rate of immune checkpoint inhibitors used alone is less than 10%[22]. This greatly increases the possibility of local recurrence if the patient cannot achieve R0 resection during surgery. In addition, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) mediate tumor immunosuppression, which also leads to the inefficiency of immunotherapy.，
- Conclusion
For this case, it is recommended to supplement NF1 gene testing and H3K27me3 immunohistochemistry (a marker of PRC2 inactivation) to determine whether there are targeted drugs available. However, due to the patient’s personal financial reasons, these tests were not performed. In addition, attention should be paid to the control of the patient’s related complications, such as scoliosis and epilepsy. Moreover, it is suggested that the patient undergo second – generation genetic counseling. The patient is currently still receiving radiotherapy, and will continue to be closely followed up in the future to closely observe the changes in the patient’s condition.
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