Ependymoma, WHO grade II Anaplastic Ependymoma, WHO grade III Christine Fuller, Medical College of Virginia, Richmond, VA

Clinical History A 5 year-old girl presented with one month history of nausea, vomiting, "blurry vision", and morning headaches. Her physical exam was significant for upbeat nystagmus and left cranial nerve VI palsy. MRI revealed a large posterior fossa mass within the forth ventricle with heterogeneous signal characteristics and contrast enhancement, as well as hydrocephalus.(Image a) A gross total resection was achieved. Total spine MRI revealed no evidence of metastases, and lumbar puncture yielded negative cytology. A representative H&E image is provided (Image b). She received radiation therapy to the tumor bed. Multiple subsequent MRIs were negative; however she was lost to follow-up for nearly a year. Approximately 28 months post therapy she presented with 2 week history of intractable headache, nausea, and vomiting. MRI showed a large heterogeneously-enhancing mass within the frontal horn of the left lateral ventricle and post-operative changes only within the posterior fossa.(Image c) A left frontal craniotomy, ventriculostomy, and lumbar puncture were performed. Gross total excision was achieved, CSF cytology was negative, and MRI of the total spine was negative for metastases. She has received radiation therapy for this second lesion and shows no evidence of recurrence / progression to date. Pertinent Laboratory Data: Representative images of the left ventricular lesion are provided (images 4-7) as well as a virtual slide for your review. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Sagittal T1 post contrast MR image showing large heterogeneous enhancing fourth ventricle mass Figure 2 Posterior fossa lesion: moderately cellular lesion with numerous perivascular nuclear-free zones Figure 3 Sagittal T1 post contrast MR image showing large heterogeneously enhancing mass involving the frontal horn of the left lateral ventricle and post-operative changes in the posterior fossa Figure 4 Frontal horn lesion: few areas of this lesion showed similar microscopic appearance to this patient's prior posterior fossa lesion (moderate cellularity and perivascular nuclear-free zones) Figure 5 Frontal horn lesion: low-power view showing regions of geographic tumor necrosis in this hypercellular tumor Figure 6 Frontal horn lesion: high-power view showing a hypercellular tumor with multiple gland-like structures with central lumen Figure 7 Frontal horn lesion: multifocal microvascular proliferation and abundant mitoses Introduction: This case explores two key concepts: 1) differentiation of ependymoma from other gliomas and cellular pediatric brain tumors, and 2) how to recognize anaplasia in ependymoma. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The lesion arising within the fourth ventricle / posterior fossa was moderately cellular, composed of a monotonous population of cells with oval to round nuclei, fine chromatin, and lacking nucleoli. Numerous perivascular nuclear free-zones were present throughout the lesion; in these areas, delicate fibrillar processes were seen radially arranged around the central blood vessels (Figure 5B). Also present were occasional small gland-like structures in which a single layer of cuboidal to columnar cells was arranged around a central lumen. Mitotic figures were uncommon, and there was no significant nuclear pleomorphism or microvascular proliferation. Few small zones of necrosis (non-pseudopalisading) were encountered. Tumor tissue was diffusely immunopositive for S100 and GFAP, the later stain highlighting the elongated thin glial processes within the perivascular zones. Synaptophysin stain was negative. Ki67 confirmed a low (1- 2%) proliferation index. The lesion that arose subsequently in the frontal horn of the left lateral ventricle was significantly more cellular overall compared to the original posterior fossa tumor, though focally less cellular areas were detected with a morphologic appearance quite similar to that lesion (Figure 5D). The majority of the frontal tumor was hypercellular with many areas of geographic necrosis (Figure 5E). Microvascular proliferation and abundant mitoses were present throughout (Figure 5G), and focally gland-like structures with central lumens (again similar to those seen in the posterior fossa tumor) were identified (Figure 5F). A pseudopapillary architecture was seen in some areas. By immunohistochemistry, the lesion was positive for S100 and GFAP. Ki67 confirmed a brisk proliferation index. Differential Diagnoses: Other gliomas: Infiltrative gliomas, Pilocytic and pilomyxoid astrocytoma Pediatric embryonal tumors: PNET/medulloblastoma, Ependymoblastoma Rare entities: Astroblastoma, Angiocentric glioma Final Diagnosis: Original posterior fossa tumor - Ependymoma, WHO grade II Frontal horn tumor - Anaplastic Ependymoma, WHO grade III Case Discussion: Ependymomas- Tumors exhibiting ependymal differentiation Subependymoma (WHO grade I) Myxopapillary ependymoma (WHO grade I) Ependymoma (WHO grade II) Cellular Tanycytic Papillary Clear cell Anaplastic ependymoma (WHO grade III) Incidence Most common tumor of the spinal cord (adults - 30s) 3rd most common pediatric CNS tumor; 1/3 brain tumors in children <3 years Most are sporadic; may be seen as part of Neurofibromatosis type 2 Clinical Findings Intracranial: signs and symptoms related to hydrocephalus and increased intracranial pressure Spinal: back pain +/- motor /sensory deficits Neuroimaging Findings Sharply demarcated Frequently with cystic component Isointense on T1 and hyperintense on T2 weighted MR imaging Variable enhancement post-contrast +/- Hemorrhage and / or calcifications Hydrocephalus Key features for recognizing ependymomas Demarcation from the surrounding CNS parenchyma Imaging Gross (surgeon) Micro Perivascular pseudorosettes Anuclear zones formed by the long fibrillary tumor cell processes in their radial arrangement around blood vessels Seen in the vast majority of cases True ependymal rosettes and canals Cuboidal or columnal epithelial-like tumor cells surrounding a true central lumen Minority of cases Ependymal-type lining seen at the periphery of tissue fragments Ancillary testing Electron microscopy Intermediate filaments Junctional complexes Microvilli +/- microlumina +/- cilia Immunohistochemistry S100, GFAP, vimentin EMA dot or ring-like positivity CD99 frequently positive (membrane or dot) Neural markers negative Lesions that may mimic ependymoma Other gliomas Infiltrative gliomas Pilocytic astrocytoma / pilomyxoid astrocytoma Pediatric embryonal tumors PNET / medulloblastoma Ependymoblastoma Really rare entities Astroblastoma Angiocentric glioma Ependymoma vs infiltrative gliomas Both may exhibit (most features dependent on grade) Variable cellularity Variable mitoses, microvascular prolif, necrosis GFAP-positive fibrillary processes Ependymomas Are solid NOT INFILTRATIVE (Imaging and micro) Have perivascular pseudorosettes +/- true ependymal canals or rosettes Ependymoma vs Pilocytic astrocytoma and pilomyxoid astrocytoma All may exhibit Variable cellularity GFAP-positive fibrillary processes Perivascular pseudorosettes Tend to be solid / demarcated lesions Ependymoma vs Pilocytic astrocytoma Ependymomas Do NOT have Rosenthal fibers or eosinophilic granular bodies (pilocytic) Do NOT have biphasic solid / loose architecture (pilocytic) Ependymoma vs Pilomyxoid astrocytoma Ependymomas Do NOT have abundant myxoid background (pilomyxoid) Are NOT positive for synaptophysin (pilomyxoid) Do NOT tend to arise in the hypothalamic region (pilomyxoid) Ependymomas versus Pediatric Embryonal Tumors Both may exhibit Hypercellularity Necrosis Many mitosis and high proliferation index Ependymomas Have more diffuse and consistent GFAP positive Are Negative for neural markers Have different types of rosettes…. Ependymoblastoma versus "The rare and obscure" Astroblastoma Rare pediatric tumor arising in the cerebral hemispheres Imaging - Well-demarcated, enhancing, often cystic Microscopic Perivascular processes are short and wide Vessels often hyalinized IHC not helpful (s100, GFAP, +/- EMA) Angiocentric Glioma (New to WHO 2007) Children / young adults Superficial cerebral cortex = Seizures Imaging- Well-demarcated, solid, non-enhancing Microscopic Perivascular pseudorosettes (radial arrangements) Longitudinal orientation of perivascular arrangements Infiltrative spindle cells resemble infiltrative glioma IHC not helpful Grading in ependymomas: An unresolved issue... WHO 2007 Anaplastic ependymoma High cellularity Brisk mitotic activity Often accompanying Microvascular proliferation Pseudopalisading necrosis Studies regarding Determination of histologic parameters that define anaplastic ependymoma (WHO grade III) and what role this grading plays in predicting patient outcomes = Inconsistent Findings Though many studies have found histologic grading to be significantly predictive of overall and/or recurrence-free survival, few observers have shown otherwise Recent correlative findings Ependymomas harboring 2 or more of the following features have been found to be strongly correlative of shortened event-free survival and grade III designation: elevated mitotic index hypercellularity with nuclear hyperchromasia and/or pleomorphism endothelial proliferation palisading necrosis So what does focal anaplasia mean??? May suggest a more aggressive biologic potential than that of typical WHO grade II ependymoma Recurrence / spread Malignant degeneration to WHO grade III We don't know yet!!! References: Tihan T, Zhou T, et al. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 2008; 21:165-177. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. Lyon: IARC; 2007. Kurt E, Zheng PP, et al. Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 2006; 106(2):388-395. Korshunov A, Golanov A, Sycheva R, Timirgaz V. The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer 2003; 100:1230-1237. Merchant TE, Jenkins JJ, et al. Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys 2002; 53(1):52-57. Schiffer D, Giordana MT. Prognosis of ependymoma. Childs Nerv Syst. 1998 Aug;14(8):357-61.