Extensive Leptomeningeal Spreading of Ependymoma in an Adult: Case Report and Literature Review

Abstract

Ependymoma is a rare adult tumor that originates from ependymal cells of the central nervous system, primarily occurring in the cerebral ventricles or the central canal of the spinal cord. In this paper, we report a case of extensive leptomeningeal seeding of ependymoma of a 39-year-old male patient, in whom the tumor was found incidentally after head trauma. The MRI exhibited diffuse leptomeningeal infiltrative lesions along with bilateral multiple cerebral sulci, basal cisterns, cerebellopontine angle, cerebellar folia. It also showed multinodular enhancing T1 low T2 high signal intensity lesions along the whole spinal cord. After the tumor biopsy at right temporal lesion, pathologic diagnosis was classic ependymoma (WHO grade 2). The patient has undergone radiation therapy and chemotherapy, and is currently maintaining a stable condition two years after surgery. This report suggests that when considering the differential diagnosis of extensive lesions both in the intracranial and intraspinal space, ependymoma should also be considered.

INTRODUCTION

Ependymoma is a glial neoplasm of ependymal cell origin primarily occurring more frequently in children than in adults [1]. It predominantly arises in the ventricles of the brain or the central canal of the spinal cord [2]. The diagnosis of ependymoma is typically made using MRI, which is the modality of choice [3]. Most ependymomas appear as well-defined tumors on imaging, but they can also exhibit various imaging features and overlap with other lesions occurring in the same location making the diagnosis challenging [4]. This case presentation aims to report a rare case of ependymoma manifesting as leptomeningeal seeding across the whole craniospinal axis.

CASE REPORT

A 39-year-old male patient visited the clinic after a brain lesion was detected during examinations conducted following a motor vehicle accident. He had no significant past medical history, and there were no neurological abnormalities observed during the examination. The MRI exhibited diffuse leptomeningeal infiltrative lesions with T2 and fluid-attenuated inversion recovery (FLAIR) high signal intensity with mild enhancement on gadolinium-enhanced T1-weighted MRI along both cerebral sulci (frontal, temporal, and occipital lobe), both cingulate sulcus, basal cistern, suprasellar cistern, cerebellopontine angle, cerebellar folia, retrocerebellar area, 4th ventricle, right lateral ventricles, and upper cervical spine (Fig. 1). It also showed multiple bilateral cranial nerve involvement, especially both VII, VIII cranial nerves and right optic nerve. There were multiple microbleeds in corpus callosum and both frontotemporal lobes. The whole spine MRI showed multinodular T1 enhancing and T2 high signal intensity lesions along the whole spinal cord, cauda equina, and lower brain (Fig. 2A and B). Positron emission tomography/computed tomography (PET/CT) showed mild and focal fluorodeoxyglucose (FDG) uptake in spinal cord and cauda equina (Fig. 2C). There were multifocal obliteration of cerebrospinal fluid (CSF) space and mild deviation of spinal cord without significant compression. The cytologic study of CSF showed negative findings for malignancy. The case was discussed in a multidisciplinary meeting. Based on clinical and radiologic correlation, several differential diagnoses were considered, including neurosarcoidosis, myxopapillary ependymoma, neurohistiocytosis, and multiple metastases from an unknown origin. To establish an accurate diagnosis, a biopsy was performed on the temporal lesion. Following the biopsy, the patient recovered without any specific complications or symptoms.

Fig. 1. The initial brain MRI (A: axial T2, B: axial FLAIR, C: axial gadolinium-enhanced T1) exhibited diffuse leptomeningeal infiltrative lesions along both cerebral sulci (frontal, temporal, and occipital lobe), both cingulate sulcus, basal cistern, suprasellar cistern, cerebellopontine angle, cerebellar folia, retrocerebellar area, 4th ventricle, right lateral ventricle. Mild enhancement was seen on gadolinium-enhanced T1-weighted MRI. FLAIR, fluid-attenuated inversion recovery.

Fig. 2. The whole spine MRI (A: sagittal gadolinium-enhanced T1, B: sagittal T2) and whole-body fusion PET-CT (C). A and B: Multinodular T1 enhancing and T2 high signal intensity lesions along the whole spinal cord, cauda equina and lower brain. There were multifocal obliteration of cerebrospinal fluid space and mild deviation of spinal cord without significant compression. C: Mild and focal FDG uptake in spinal cord and cauda equina (arrows). PET/CT, positron emission tomography/computed tomography; FDG, fluorodeoxyglucose.

The pathological examination revealed a small round cell tumor, suggestive of ependymoma. The tumor exhibited a broad papillary pattern and a ciliated ependymal lining. Distinctive pseudorosettes and occasional true rosettes were also observed. The mitotic rates were observed to be 1–2 mitoses per 10 high-power fields. The Ki-67 labeling index was also low, ranging 3%–5%. Immunohistochemical analysis revealed positive staining for glial fibrillary acidic protein (GFAP) and S-100. Additionally, dot-like positivity was observed for epithelial membrane antigen (EMA) and D2-40 (Fig. 3). Based on the findings mentioned above, the comprehensive diagnosis of ependymoma, classic type (WHO grade 2), was made.

Fig. 3. Pathological and immunohistochemical findings. A: The tumor exhibited a broad papillary pattern and a ciliated ependymal lining (H&E, ×20 magnification). B: Distinctive pseudorosettes and occasional true rosettes were also observed (H&E, ×40 magnification). C: Immunohistochemical analysis revealed positive staining for glial fibrillary acidic protein (GFAP, ×40 magnification). D: Positive staining for S-100 (×40 magnification). E: Dot-like positive staining for epithelial membrane antigen (EMA, ×40 magnification). F: Dot-like positive staining for D2-40 (×40 magnification).

A multidisciplinary tumor board discussed the case to establish further treatment strategies for the patient. It was decided to proceed with radiation therapy and chemotherapy using temozolomide. Additionally, regular follow-up examinations were planned to monitor the patient’s progress. We performed craniospinal irradiation using intensity-modulated radiation therapy (IMRT) with a total dose of 4,500 cGy delivered in 25 fractions. Subsequently, a boost of 900 cGy in 5 fractions was administered to the brain tumor bed. Following the completion of radiation therapy, the patient is undergoing only regular follow-up examinations without adjuvant chemotherapy. The patient is maintaining a normal lifestyle without any significant neurological abnormalities or symptoms. The MRI examination performed 18 months after surgery indicates that the lesions were improved and remained stable (Fig. 4).

Fig. 4. The brain and spine MRI 18 months after radiotherapy (A: axial T2, B: axial FLAIR, C: axial gadolinium-enhanced T1, D: sagittal whole spine MRI). A-C: Slightly improvement of ependymoma at the basal cisterns, both frontal and occipital sulci, both cerebellar hemispheres, and right lateral ventricle. D: Decreased in extent of multinodular gadolinium-enhancing T1 and T2 high signal intensity lesions along the whole spinal cord and cauda equina.

DISCUSSION

Ependymoma accounts for 1.6%–1.8% of all primary central nervous system tumors and occurs more frequently in males than females. It is also more commonly seen in children compared to adults [5,6,7]. The annual incidence rate of ependymoma is reported to be approximately 0.29 to 0.6 per 100,000 persons [8]. Ependymomas have a tendency to remain asymptomatic for a prolonged period, leading to delayed detection. In cases of intracranial ependymoma, symptoms such as headaches, seizures, nausea, vomiting, balance abnormalities, and visual disturbances may occur. On the other hand, spinal ependymoma can manifest with symptoms such as low back pain, leg pain, sacral pain, leg weakness, or sphincter dysfunction.

The site of occurrence of ependymoma varies depending on the age of the patient. In children, approximately 90% of cases occur in the intracranial region, while in adults, about 65% of cases originate in the spinal cord [1,9]. In addition to the ventricle walls and central canal, ependymoma has been reported to occur in atypical locations such as extra-axial cerebral localization, cerebellopontine angle, pineal region, sella turcica, and hypothalamus [4,10,11]. Ependymoma originating from outside the central nervous system (extracranial, extraspinal space) is indeed rare but has been reported. It predominantly occurs in children and young adults, and cases of ependymoma arising in the sacrum, mediastinum, and ovaries have been documented in the literature [12]. In many cases, ependymoma tends to exhibit a compressive pattern of growth rather than an infiltrative pattern [13]. In this case, where lesions were found in both the intracranial and spinal canal simultaneously, it is difficult to determine which location is the primary lesion.

Imaging studies of ependymoma can demonstrate a wide range of appearances. On CT, ependymomas can appear iso-, hypo-, or hyperdense. They may also show heterogeneous enhancement on contrast-enhanced CT scans [14]. CT imaging is useful for detecting calcifications, which are commonly observed in subependymomas. However, MRI is considered the gold standard for diagnosing ependymomas. On MRI, ependymomas typically appear as well-circumscribed masses with specific characteristics such as low T1 signal, high T2 signal, intermediate to high FLAIR signal, and may exhibit features such as cystic formations, calcifications, hemorrhage, and necrosis [15,16]. Spinal cord ependymomas tend to exhibit more distinct borders on imaging. They can show cyst formation and T2 hypointensity of the cyst wall, known as a “hemosiderin cap,” which is caused by blood products. Additionally, associated syringomyelia, a condition characterized by the presence of a fluid-filled cavity within the spinal cord, is commonly observed in spinal cord ependymomas [17].

The definitive diagnosis of ependymoma is made through pathologic examination. It is characterized as a well-circumscribed tumor composed of ependymal differentiated cells. The tumor cells typically display a monomorphic round to oval appearance with speckled chromatin. Additionally, perivascular pseudorosettes and true ependymal rosettes may be present in the histological findings [18]. Recent studies have extensively investigated the molecular changes in ependymoma, leading to significant changes in its diagnosis and classification. In the WHO 2021 classification, ependymoma is classified into 10 subgroups based on both molecular features and histological features. This incorporation of molecular characteristics has provided a more comprehensive understanding of the disease and has contributed to improved classification and management of ependymoma [19]. It has been classified into three anatomical locations (supratentorial, posterior fossa, spinal). The supratentorial compartment includes supratentorial ependymoma, ZFTA fusion-positive, and supratentorial ependymoma, YAP1 fusion-positive. Posterior fossa ependymoma is divided into two groups: posterior fossa group A (PFA) and posterior fossa group B (PFB). Group PFB is characterized by high expression of H3K27me3 and primarily occurs in adolescents and adults. On the other hand, group PFA is characterized by low expression of H3K27me3 and mainly occurs in infants and children [20]. The spinal ependymomas include classical ependymomas (WHO grade 2 and 3) and myxopapillary ependymoma (WHO grade 2). These subtypes are more commonly observed in adults. Spinal ependymoma, MYCN-amplified is identified as an aggressive subgroup that primarily occurs in young adults and adolescents [21,22]. In this case, molecular subgrouping was not performed, indicating a need for further research and investigation in the future.

Treatment options for ependymoma include surgical resection, radiation therapy, and chemotherapy. It is important to tailor the treatment approach to each patient’s specific situation and the extent of the tumor. The primary goal of surgery in ependymoma is complete resection while preserving neurological function [23,24]. In intracranial ependymoma, the likelihood of achieving gross total resection is higher for supratentorial tumors compared to infratentorial tumors. Tumors arising from the floor or lateral portion of the fourth ventricle have a higher risk of postoperative deficits compared to tumors arising from the lateral portion alone. Therefore, there is a higher possibility of performing subtotal resection in cases where tumors arise from the floor or lateral portion, in order to minimize the risk of postoperative deficits [5]. Considering the impact of gross total resection on prognosis, a second-look surgery may be considered for cases of intracranial ependymoma where residual tumor remains [25]. However, as in this case, there are instances where surgical resection is not feasible. It is important to note that there are situations where complete surgical removal is not possible due to various factors such as tumor location, size, or involvement of critical structures. Additionally, during surgical resection, it is crucial to be mindful of the risk of seeding, which refers to the potential spread of tumor cells caused by the surgical procedure itself [26].

Radiation therapy is recommended after surgery, in cases with WHO grade III (anaplastic) ependymomas regardless of the extent of resection, and in cases with WHO grade II ependymomas where complete tumor resection is not feasible or if there is evidence of residual or recurrent disease [25]. The benefit of postoperative radiotherapy is clear in terms of local control and overall survival rate [27]. For Grade 3 or incompletely resected Grade 2 tumors, a recommended radiation dose of 59.4 Gy (1.8 Gy per fraction) is generally advised. However, in cases involving children younger than 18 months or children with altered neurological status, the radiation dose can be reduced to 54 Gy [28,29]. The potential toxicity of radiotherapy is an important consideration in the treatment of ependymoma. To reduce late sequelae and minimize radiation-related side effects, techniques such as IMRT are employed. Additionally, efforts are being made to explore the use of proton therapy, which has the potential to further reduce toxicity by delivering radiation with greater precision and sparing normal tissues even more effectively [30].

While chemotherapy is newly diagnosed ependymoma remains controversial, it may be considered in cases where there is incomplete resection or evidence of tumor progression or recurrence [15]. Radiation therapy may be reluctant for very young children due to the potential long-term side effects on developing tissues. In such cases, postoperative chemotherapy may be considered as an alternative to radiation therapy. Various combinations of chemotherapy drugs are used in the treatment of ependymoma, including etoposide, vincristine, cyclophosphamide, platinum derivatives (such as cisplatin or carboplatin), high-dose methotrexate, and temozolomide [5,31,32,33,34]. In this case, temozolomide was considered for chemotherapy; however, due to the patien’s stable condition, it has not been administered, and the patient is currently under observation. The treatment plan should be individualized based on various factors such as tumor size, location, extent of spread, age of the patient, and underlying disease. A multidisciplinary approach involving neurosurgeons, radiation oncologists, neuro-oncologists, pathologists, and radiologists is essential in determining the optimal treatment strategy for each patient.

The diagnosis of ependymoma in adults is very challenging. Ependymoma has the potential to spread into the intracranial or intraspinal spaces through the leptomeninges. Therefore, when encountering a patient with extensive leptomeningeal seeding, we should consider the possibility of ependymoma in the differential diagnosis.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.