Extraneural metastatic ependymoma: distant metastasis to the pleura, lungs, lymph nodes and bone.

Ependymomas are neuroepithelial tumours arising from ependymal cells surrounding the cerebral ventricles that rarely metastasise to extraneural structures. This spread has been reported to occur to the lungs, lymph nodes, liver and bone. We describe the case of a patient with recurrent CNS WHO grade 3 ependymoma with extraneural metastatic disease. He was treated with multiple surgical resections, radiation therapy and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space and lymph nodes.

Survival and Prognostic Factors of Adult Intracranial Ependymoma: A Single-institutional Analysis of 236 Patients.

Adult intracranial ependymomas (EPNs) are extremely rare brain tumors. Currently, clinical and molecular factors that could inform individualized treatment strategies are still lacking for EPNs in this age group. The aim of this study was to investigate potential prognostic indicators and rational therapeutic management in a large cohort of adult intracranial EPNs. Adult patients who underwent resection of World Health Organization (WHO) grade II or III intracranial EPNs were included. The demographic features, clinicopathologic manifestations, molecular subgroups, and outcomes were retrospectively analyzed. Overall survival and progression-free survival were calculated using the Kaplan-Meier analysis. Potential prognostic indicators were identified using multivariable Cox proportional hazards model. This cohort included 236 adult patients with a mean age of 36.2 years (range: 18 to 72 y) at diagnosis. The tumor location was supratentorial (ST) in 102 (43.2%) and infratentorial in 134 (56.8%). Pathologic analysis revealed 43.1% of ST-EPNs with RELA fusion and 88.1% of posterior fossa ependymomas (PF-EPNs) with positive H3K27me3 staining. Gross total removal was achieved in 169 cases (71.6%). During follow-up, 97 (41.1%) patients had disease progression and 39 (16.5%) died. Kaplan-Meier analysis showed that patients with H3K27me3-positive PF-EPN had excellent survival, whereas patients with RELA fusion-positive ST-EPN or H3K27me3-negative PF-EPN had poor prognosis (progression-free survival: P=1.3E-16, overall survival: P=2.5E-12). Multivariate analysis showed that molecular subgroup, extent of resection, and Ki-67 index were strong independent prognostic indicators. In conclusion, our study provides essential information on the prognostic prediction of adult intracranial EPNs that will assist in establishing appropriate risk stratification and individualized treatment strategies in future clinical trials.

Metastatic myxopapillary ependymoma treated with immunotherapy achieving durable response.

Myxopapillary ependymoma (MPE) is a rare glial tumour mainly located in the areas of the conus medullaris, cauda equina and filum terminale of the spinal cord. Ectopic MPE tends to behave more aggressively and distant metastases are often seen. Unfortunately, no standard treatment options are established as only small series of treated patients and a few reported cases are available in the literature. We report the case of a 25-year-old woman who was initially diagnosed with a metastatic MPE, with multiple bilateral lung metastases. She was treated with an investigational monoclonal antibody antiprogrammed cell death protein 1, called tislelizumab (BGB-A317), following surgical resection of the perisacral primary mass. The response was long-lasting and side effects nil. Immunotherapy is a treatment modality to be considered in patients with rare tumours.

Spinal Intradural Extramedullary Ependymoma with Intracranial Metastasis and Leptomeningeal Spread: A Case Report and Comprehensive Review of Literature.

Dorsolumbar intradural extramedullary ependymoma is a rare entity. Spinal metastases in patients with intracranial ependymoma are well described, but it is extremely rare for a spinal ependymoma to metastasize to brain. We describe a case of aggressive dorsolumbar intradural extramedullary ependymoma mimicking arachnoid cyst radiologically, which developed intracranial metastasis.

TERTp Mutation Detection in Plasma by Droplet-Digital Polymerase Chain Reaction in Spinal Myxopapillary Ependymoma with Lung Metastases.

BACKGROUND: Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. CASE DESCRIPTION: We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. CONCLUSIONS: Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors.

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.

BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma.

BACKGROUND: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. METHODS: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. RESULTS: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. CONCLUSIONS: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00634231.

Supratentorial extraventricular anaplastic ependymoma with extracranial metastasis.

Ependymoma is a relatively rare malignancy accounting for 2.0% of all primary central nervous system tumors in adults. Extracranial metastasis is a very uncommon complication of gliomas, especially of anaplastic ependymomas. The objective of this paper is to show that ependymomas can metastasize to soft tissue and lymph nodes as well as to share our approach to this challenge. We report a male patient with anaplastic ependymoma that recurred, metastasizing to the neck and lymph nodes. Metastatic disease was diagnosed based on clinical presentation of a palpable nodule on the right neck and diffuse cervical lymphadenopathies. A biopsy was obtained and pathology revealed anaplastic ependymoma. Whole-body fluorodeoxyglucose positron emission tomography scan showed metastatic disease in the right mastoid region with diffuse uptake in the cervical lymph nodes. Clinical and radiologic response was achieved after three chemotherapy cycles of etoposide, cisplatin, vincristine, and cyclophosphamide. This case highlights extracranial metastasis to the soft tissue as an atypical presentation of recurrent anaplastic ependymoma. Other reported instances of extracranial metastatic ependymoma with this presentation are discussed. The possible metastatic pathways of intracranial disease are discussed. It also illustrates how extracranial disease remains stable with systemic chemotherapy.

Extraneural metastasis of an ependymoma: a rare occurrence.

Extraneural metastases of ependymoma are very rare, and have been reported in the lungs, lymph nodes, pleura, mediastinum, liver, diaphragmatic muscle, and bone. We describe the radiological findings of pathologically proven lung metastases from an anaplastic ependymoma. The tumor which arose in the posterior fossa was first diagnosed in 2007 when first surgical resection was performed outside our institute. Multiple operations were performed after that due to tumor relapse. Multiple lung nodules were discovered incidentally during a VP shunt survey. Biopsy from the lung nodules displayed identical histomorphology to the primary brain tumor.

Spinal ependymoma with regional metastasis at presentation.

BACKGROUND: Ependymomas are the most common glial neoplasms in the spinal cord. However, spinal cord ependymomas presenting with regional dissemination along the neuroaxis are rare, with a yet undetermined standard of care. We retrospectively evaluated the management and outcomes of patients who were diagnosed with spinal ependymoma with regional metastases at presentation (SERMP). METHODS: Between 2002 and 2012, 16 patients with regionally metastatic spinal ependymomas were diagnosed and treated. The patients were retrospectively divided into two groups according to tumor grading and histological features. Nine patients were diagnosed with myxopapillary ependymomas (MPE), and seven patients were diagnosed with other low-grade ependymomas. RESULTS: With a median follow-up of 46.4 months, 13 out of 16 patients had no postsurgical recurrence/progression of the disease. In three patients, the disease recurred/progressed, leading to death in one patient. There was no correlation between gross total removal (GTR) of the main tumor, or resection of the main lesion and the metastatic foci and increased progression free survival in patients of the MPE group. There was an advantage for patients diagnosed with other low-grade ependymomas. Adjuvant radiotherapy did not prove beneficial. CONCLUSIONS: SERMP has a relatively benign course. Achieving GTR of both the main lesion and the metastases is preferable, but should not be achieved at any cost, especially in MPE interfering with the conus medullaris. The benefit of adjuvant radiotherapy remains unproven.

Myxopapillary ependymoma in the third ventricle area and sacral canal: dropped or retrograde metastasis?

Myxopapillary ependymoma (MPE) is a rare type of central nervous system neoplasm mostly located in the cauda equina and filum terminale regions. A previously healthy 22-year-old Chinese man presented with the first case of MPE in the third ventricle area and sacral canal initially manifesting as spinal cord compression. The patient was admitted with pain in the right lower extremity for 5 months and encopresis for 3 months. Magnetic resonance imaging of the lumbar spine revealed an intradural lesion at the S2 level. The patient accordingly underwent lumbar laminectomy surgery and gross total resection of the tumor. Shortly after surgery, a mass was found in the third ventricle. The patient subsequently underwent further craniotomy surgery, and the histopathological examination eventually revealed MPE. MPE usually undergoes intracranial retrograde metastasis, but we consider that our case was a dropped metastasis of the primary intracranial MPE. Neurosurgeons need to be aware of intracranial MPEs in patients with isolated spinal lesions, and long-term follow-up is important in patients who are diagnosed with MPE after surgical excision.

Mortality is higher in patients with leptomeningeal metastasis in spinal cord tumors.

UNLABELLED: Spinal cord tumors are a rare neoplasm of the central nervous system (CNS). The occurrence of metastases is related to poor prognosis. The authors analyzed one series of metastasis cases and their associated mortality. METHODS: Clinical characteristics were studied in six patients with intramedullary tumors with metastases in a series of 71 surgical cases. RESULTS: Five patients had ependymomas of which two were WHO grade III. The patient with astrocytoma had a grade II histopathological classification. Two patients required shunts for hydrocephalus. The survival curve showed a higher mortality than the general group of patients with no metastases in the CNS (p<0.0001). CONCLUSION: Mortality is elevated in patients with metastasis and greater than in patients with only primary lesions. The ependymomas, regardless of their degree of anaplasia, are more likely to cause metastasis than spinal cord astrocytomas.

Mortality is higher in patients with leptomeningeal metastasis in spinal cord tumors / Mortalidade é mais elevada na disseminação metastática leptomeníngea em tumores da medula espinhal

Spinal cord tumors are a rare neoplasm of the central nervous system (CNS). The occurrence of metastases is related to poor prognosis. The authors analyzed one series of metastasis cases and their associated mortality. METHODS: Clinical characteristics were studied in six patients with intramedullary tumors with metastases in a series of 71 surgical cases. RESULTS: Five patients had ependymomas of which two were WHO grade III. The patient with astrocytoma had a grade II histopathological classification. Two patients required shunts for hydrocephalus. The survival curve showed a higher mortality than the general group of patients with no metastases in the CNS (p<0.0001). CONCLUSION: Mortality is elevated in patients with metastasis and greater than in patients with only primary lesions. The ependymomas, regardless of their degree of anaplasia, are more likely to cause metastasis than spinal cord astrocytomas.

Tumores da medula espinhal são neoplasias raras do sistema nervoso central (SNC). A ocorrência de metástases é relacionada a pior prognóstico. Os autores analisaram uma série de casos de metástases e a mortalidade relacionada. MÉTODO: Foram estudadas as características clínicas em seis pacientes com metástases tumorais numa série de 71 casos operados. RESULTADOS: Cinco pacientes tinham ependimomas e dois dos quais foram grau III pela classificação da OMS. O paciente portador de astrocitoma tinha classificação histopatológica de grau II. Dois pacientes necessitaram de derivação devido à hidrocefalia. A curva de sobrevivência mostrou mortalidade mais elevada no grupo de pacientes com disseminação pelo SNC (p<0,0001). CONCLUSÃO: A mortalidade, além de elevada em pacientes com metástases, é maior do que em pacientes apenas com lesão primária. Os ependimomas, independentemente do seu grau de anaplasia, costumam causar mais metástases do que os astrocitomas medulares.

Extraneural ependymoma: distant bone, lung, liver, and lymph node metastases following bevacizumab.

Extraneural metastases of ependymoma are rare, and have been reported in the lungs, lymph nodes, pleura, mediastinum, liver, diaphragmatic muscle, and bone. We report a case of anaplastic ependymoma with distant metastases to the vertebral bones, lungs, liver, and lymph nodes following treatment with bevacizumab. Recent research has hypothesized that angiogenic tumors may develop means of resistance to antiangiogenic therapies, and some evidence suggests potential for antiangiogenic therapies to promote additional means for cancer spread. Nevertheless, antiangiogenic therapies continue to demonstrate potential as potent therapies for the treatment of many cancers, and should continue to be researched for future uses.

Rim and flame signs: postgadolinium MRI findings specific for non-CNS intramedullary spinal cord metastases.

BACKGROUND AND PURPOSE: No highly specific MR imaging features distinguishing ISCMs from primary cord masses have been described. Our purpose was to retrospectively compare peripheral enhancement features on postgadolinium MR imaging of ISCMs with primary intramedullary cord masses. MATERIALS AND METHODS: A consecutive group of patients with firmly diagnosed ISCM (45 patients with 64 ISCMs) and a comparison group with consecutive pathologically proved primary intramedullary spinal cord masses (64 patients with 64 primary spinal cord masses: ependymoma, astrocytoma, hemangioblastoma, ganglioglioma, and cavernous malformation) were included. MR images were evaluated for 2 specific signs on postgadolinium images: a "rim" sign (more intense thin rim of peripheral enhancement around an enhancing lesion) and "flame" sign (ill-defined flame-shaped region of enhancement at the superior/inferior lesion margins). The frequency of rim and/or flame signs in ISCMs and primary cord masses was compared (χ2 test). For ISCMs, the maximal dimension of the enhancing lesion was correlated with the presence of rim or flame signs (t test). RESULTS: Rim and flame signs, alone and in combination, were seen more frequently in ISCMs than in primary cord masses (P<.0001 for each). Specificity and sensitivity, respectively, for diagnosing ISCMs among spinal cord masses on a per-patient basis were the following: rim sign, 97%, 47%; flame sign, 97%, 40%; at least 1 sign, 94%, 60%; and both signs concurrently, 100%, 27%. In the ISCM group, the presence of either a rim or flame sign correlated with a larger measured maximum enhancing lesion size (P=.0065 and P=.0012, respectively). CONCLUSIONS: The rim and flame signs are common in and specific for ISCM and are rare in primary spinal cord masses.

Metronomic cyclophosphamide with cisplatin and bevacizumab: a new chemotherapeutic regimen for refractory anaplastic ependymoma.

UNLABELLED: Anaplastic ependymoma is a rare brain tumor, induced both in the brain and the spine. The treatment relies on surgery and radiotherapy. Upon failure of these treatments, chemotherapy has modest effects. Here, we report two cases of anaplastic ependymoma with prolonged radiological and clinical responses to a metronomic cyclophosphamide, cisplatin and bevacizumab regimen. Two patients with anaplastic ependymoma, refractory to surgery and radiotherapy were proposed for a chemotherapeutic treatment. These patients had both spina and brain nodules. Neurological symptoms included arm deficiencies and paraparesia. RESULTS: Six cycles of the metronomic cyclophosphamide (50 mg per day, daily), cisplatin (100 mg/m(2) every four weeks) and bevacizumab (10 mg/kg every two weeks), as a chemotherapeutic regimen, induced both radiological response on magnetic resonance imaging and clinical response with neurological deficiency regression. At one year, the patients were still under maintenance therapy with metronomic cyclophosphamide and cisplatin. This treatment still continues to control tumor progression and symptoms. CONCLUSION: This is the first report showing an impressive efficacy of metronomic the cyclophosphamide, cisplatin and bevacizumab chemotherapeutic regimen for the treatment of refractory anaplastic ependymoma.

EGFR as a predictor of relapse in myxopapillary ependymoma.

Myxopapillary ependymoma (MPE) is a rare subtype of ependymoma in children. Though classified as a Grade I tumor, their unpredictable behavior and propensity for local and disseminated recurrence poses a therapeutic challenge. Till date no predictive molecular markers exist for such recurrence, especially with dissemination. We demonstrated that Epidermal Growth Factor Receptor (EGFR) expression was seen in relapsed MPE both at diagnosis and at recurrence and none in the nonrecurring tumors. This finding suggests EGFR could be a predictive biomarker for recurrence in MPE.

Inguinal lymph nodal metastasis of myxopapillary ependymoma confirmed by fine-needle aspiration cytology, biopsy, and immunohistochemistry: case report.

Ependymoma (EP) rarely metastasizes outside the central nervous system. Inguinal nodule metastasis of EP more than 10 years after surgical resection and radiotherapy is extremely rare. We report a man aged 38 years who underwent surgery for lumbosacral myxopapillary EP at the age of 22 years and was treated with several cycles of radiotherapy. The patient was reoperated for residual tumor and received two complete cycles of radiotherapy for 11 years. Biopsies were always diagnosed as myxopapillary EP. Five years after the last surgical excision, the patient developed abdominal pain and inguinal lymphadenopathy. Biopsy was performed by fine-needle aspiration and was proven malignant epithelial neoplasm with a myxoid background, was diagnosed as metastasis of EP. Biopsy showed an anaplastic EP grade III. EP is often recurrent at the primary site but can seed on the entire cerebrospinal axis. We describe the clinical features of this rare lesion and particularly emphasize the need for long-term follow-up, for more than 10 years after the initial treatment, in patients with EP and malignant transformation after radiotherapy.