Ependymoma

Etiology

While ependymomas that arise from different regions of the CNS are histologically similar, their clinical course often varies. Histological classification alone has not provided consistent and reliable survival outcomes in retrospective studies, meaning that ependymomas with similar histological grades may follow a substantially different clinical course. Recent studies suggest that these tumors may be categorized based on different populations of progenitor cells, which would explain different clinical courses in tumors with the same histological grade.[2] Several genetic abnormalities have been found to correlate with ependymoma and comprise large genomic regions.[3] Some of these studies have demonstrated that ependymomas correlate with distinct oncogenic products and molecular subgroups which may correlate more accurately with clinical outcomes compared with histologic classification alone.[4]

Epidemiology

Ependymomas affect all age groups, with a higher frequency in children.[1] It is the third most common brain tumor in pediatric patients.[3]

As per the Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report for CNS tumors from the years 2011 to 2015, ependymal tumors represent 1.7% of all brain and CNS tumors, with a median age of 44 years.[5]

In childhood, brain tumors are the primary cause of death associated with solid tumors. The most common pediatric brain tumors being medulloblastoma, pilocytic astrocytoma, brainstem glioma, and ependymoma.[6]

Pathophysiology

Based on genetic mutations and variations, ependymomas are classified as follows:

Posterior fossa (PF):

• PF-EPN-SE (subependymoma)
• PF-EPN-B (group B)
• PF-EPN-A (group A)

Supratentorial (ST):

• ST-EPN-SE (subependymoma)
• ST-EPN-YAP1 (YAP1 fusions)
• ST-EPN-RELA (RELA fusions)

Spinal ependymomas:

• SP-EPN-MPE (myxopapillary)
• SP-EPN-SE (subependymoma)
• SP-EPN

Histopathology

As with other CNS tumors, the TNM system of classification does not apply to ependymomas as they rarely spread outside of the CNS, and the WHO classification for CNS tumors is the current standard used to classify these ependymomas:[1][7]

• Grade I, slow-growing tumors which are often considered benign, including subependymomas and myxopapillary ependymomas:
  • Subependymomas typically arise in the ventricular walls, most commonly in the fourth or lateral ventricles - they are histologically characterized by a hypocellular tissue presenting clusters of cells with a bland nucleus surrounded by a glial matrix.
  • Myxopapillary ependymomas most commonly arise in the cauda equina, filum terminale, or conus medullaris, and present histologically as pseudopapillary structures with mucin-rich microcysts, the cells are cuboidal and radially arranged surrounding a myxoid stroma.
• Grade II are ependymomas presenting with high cellularity and papillary structures. Cells are arranged regularly and present a clear cytoplasm.
• Grade III, are anaplastic ependymomas, presenting with abundant mitotic cells with pseudopalisading necrosis.

History and Physical

As ependymomas arise within different CNS compartments, their clinical presentation may vary from acute onset increased intracranial pressure causing nausea and vomiting, to a more chronic and insidious clinical course.[4]

Ependymoma is a histological diagnosis, and it most commonly presents in three major anatomical sites: supratentorial, spinal cord, and infratentorial.[8]

Ependymoma is commonly suspected in adult patients suffering prolonged clinical courses, who present a non-enhancing and well-demarcated intraventricular lesion on brain imaging, isodense in computed tomography, and isointense on T1 images on magnetic resonance imaging (MRI).[9]

Evaluation

Traditionally, ependymomas are classified using the World Health Organization (WHO) system to classify tumors of the nervous system. This histological grading commonly aids in predicting the clinical and biological behavior of central nervous tumors. In ependymoma, however, the molecular and genomic profiles may provide more accurate information than only using histological grade.[10]

Tumor grading using the WHO classification system for nervous system tumors is based on different histological grades, this classification by itself would often not provide a reliable estimate of clinical course in patients with ependymoma. With increasing information about molecular pathogenetic mechanisms in ependymomas, the 2016 classification for nervous system tumors from WHO now includes in their classification the presence or absence of specific genetic alterations, RELA fusion-positive or negative, for ependymomas.[10][11]

There are nine molecular subgroups described in ependymomas, which correlate with different anatomical locations, genetics, and demographic characteristics. These new findings offer the opportunity of potentially improving the classification, management, and prognostic information for ependymomas based on their molecular subgroup.[8]

No current molecular or immunohistochemical markers are in routine use in the diagnostic workup for patients with ependymoma.[8]

Treatment / Management

Ependymal tumors are rare, constituting 1.7% of all brain tumors, as reported in the most recent CBTRUS statistical report; this poses a challenge in defining the optimal management for these entities. Retrospective studies have described improved survival in patients undergoing resection with adjuvant radiation therapy. There is minimal and limited evidence supporting chemotherapy for adult ependymomas.[4](B3)

No established guidelines use the molecular subgroups to guide the treatment of ependymoma. The current consensus, however, recommends that patients with PF-EPN-A positive ependymoma, who are older than 12 months of age, undergo maximal safe micro-neurosurgical removal in addition to local radiotherapy.[8](B3)

For intracranial ependymomas, surgery is typically the mainstay treatment. Complete resection without residual disease has presented better clinical outcomes and overall survival than partial resection. As discussed previously, there is insufficient evidence to support the use of chemotherapy.[8](B3)

Differential Diagnosis

The differential diagnosis for tumors in the posterior fossa includes astrocytoma, medulloblastoma, choroid plexus tumors.

For supratentorial tumors, the differential includes glial tumors, choroid plexus carcinoma or papilloma, and embryonal tumors.[10]

Prognosis

The extent of surgical resection for intracranial ependymomas has been the most reliable and consistent independent prognostic factor. Intracranial ependymomas show a low metastatic potential and predominantly present a locally invasive histological pattern. Ependymomas that fall within the histological grade III from the WHO classification have correlated with a worse outcome than grade II.[12][13]

Patients who undergo complete resection without signs of residual disease have presented a better outcome and overall survival compared to patients who undergo partial resection. For this reason, treatment typically consists of aggressive surgical excision.[8]

Across the different subgroups, infratentorial ependymomas generally have an excellent prognosis, even without treatment. Supratentorial ependymomas, however, often present a higher histological grade and have a lower survival rate despite treatment with resection and adjuvant radiation.[4]

Prognosis varies for pediatric patients and will be subject to location, type of treatment, and pathological classification. A previous study showed that gross total resection had the best overall and progression-free survival. Patients with WHO classification grade II had improved overall survival after gross total resection in addition to external beam radiation therapy, and improved progression-free survival after gross total resection alone. Patients with WHO classification grade III had improved overall survival after subtotal resection in addition to external beam radiation therapy. While progression-free survival was better in patients with infratentorial tumors following subtotal resection in addition to external beam radiation therapy.[14][15][16][17]

Complications

Patients who are long-term survivors of CNS tumors may present a wide diversity of complications, including neurological deficits, cognitive limitations, sensorineural hearing loss, endocrine and growth abnormalities, and secondary malignancies. Adult patients may present long-term complications, most commonly fatigue, numbness and tingling, pain, and disturbed sleep.[15][16][18][19]