Introduction
Ependymomas are glial tumors that derive from ependymal cells and can arise anywhere within the central nervous system. As noted in trends in central nervous system tumor, the overall incidence of ependymoma increased from 2000 to 2010 with an annual percent change of 2.1%.1 Ependymomas are rare primary gliomas that affect both children and adults.In recent years, the molecular biomarkers gaining importance in providing ancillary and diagnostic information as per WHO CNS tumor classification 2021.2 Massimino M et al studied on an integrated molecular and clinical characterization with a long term follow-up was done.3
The anatomic localization forms the basis of the new WHO (2021) classification scheme for ependymomas.as in the supratentorial, posterior fossa, and spinal compartments. As compared with intracranial ependymomas, spinal ependymomas are less frequent.The supratentorial ependymoma molecular group includes those with fusion genes involving ZFTA (formerly C11orf95) or fusion genes involving YAP1.4 Our study adds to the knowledge about supratentorial ependymoma tumor’s behavior, histomorphological features and recent update.
Case Report
A 28 year old male patient came with complaints of bilateral upper limb and lower limb weakness, head ache, accompanied by vertigo, vomiting, twice focal seizures over the past two to three months. Associated with lethargy and dizziness. He had no history of hypertension, diabetes. On physical examination, spasticity present in both lower extremity L>R and left unilateral grade II facial nerve palsy. Previous history of transient ischemic attack was there for which treatment was received. Clinical diagnosis was give as right perital space occupying lesion.? cerebral hematoama, ? neoplastic.
CT Brain (Plain) findings showed a large heterodense lesion noted in the right fronto-parietal lobe with hypodense areas and extensive calcifications within (Figure 1 ). Thereis evidence of extensive surrounding hypodensity (edema). The lesion is causing effacement of adjacent cortical sulcal spaces and mass effect on adjacent brain parenchyma and ipsilateral lateral ventricle leading to a midline shift of (~ 5 mm) towards left side. Features likely suggestive of malignant etiology. Suggested differentials were neurocytoma, ependymoma, astrocytoma.
Figure 1
CT Brain shows a large heterodense lesion noted in the right fronto-parietal lobe with hypodense areas and extensive calcifications within
MRI Brain (Plain + Contrast) Axial T1W, FLAIR & T2W: Coronal FLAIR; Sagittal T1W; Diffusion findings showed a well-defined, multilobulated, intra-axial altered signal intensity lesion measuring 4.3 × 3.7 x 4.8 cm is noted in right parietal lobe involving the post central gyrus. There is significant surrounding non enhancing FLAIR hyperintensity (edema) extending to adjacent body of corpus callosum and minimally to periventricular white matter of contralateral white matter of parietal lobe causing effacement of adjacent cortical sulcal spaces and mass effect on body and posterior horn of ipsilateral lateral ventricle with a midline shift of (5 mm) towards left side. Signal characteristics: T1 - Iso to hyperintense signal, T2WI/FLAIR- heterogeneously hyperintense signal with multiple T2 hyperintensities (cystic/necrosis) within. DWI (Diffusion-weighted magnetic resonance imaging)/ADC(apparent diffusion coefficient) showed patchy areas of diffusion restriction. GRE (gradient echo) showed few subcentimetric areas of blooming (largest measuring ~ 8.3 x 9.4 mm; AP x T, along the posterolateral aspect of the lesion) (confirmed on CT) - calcifications. Post contrast - Solid component showed heterogenous post contrast enhancement.
On Spectroscopy there is elevated choline peak with increased choline: creatinine ratio and attenuation N-acetylaspartate peak in the region of interest. Brainstem shows normal morphology and signal intensity. Impression given was a well-defined heterogenously enhancing multilobulated, intra-axial lesion in right parietal lobe involving the post central gyrus with areas of calcification and necrosis with elevated choline peak and increased choline: creatinine ration with attenuated NAA peak on magnetic resonance spectroscopy. Significant perilesional edema seen. Features suggestive of primary malignant glial neoplasm.
He underwent right craniotomy with excision of space occupying lesion. On gross examination soft, gray-red, fleshy lesion with calcification were observed. (Figure 2 a). Histopathologically showed a heterogeneous well-delineated tumour composed of cells with monomorphous ovoid nuclei and fine punctate chromatin. In areas pseudorosettes with tumor cells arranged radially around blood vessels with anuclear zones were noted. Extensive intratumoral calcification was noted (Figure 2b, Figure 3 a,b,c,d ).
Figure 2
a): Gross specimen- soft, gray-red, fleshy lesion with calcification; b): Histopathologically show cellular tumor having monomorphic round to oval cells with speckled chromatin and vascularity (H& E stain, 40x)
Figure 3
a): Tumour with papillary structures composed of cells with monomorphous ovoid nuclei and fine punctate chromatin; b): Tumour with extensive intratumoral calcification, c): in areas pseudorosettes with tumor cells arranged radially around blood vessels and d): true ependymal rosette. (H& E stain, 400x)
The tumour cells was positive for glial fibrillary acid protein (GFAP) immunostaining,ATRX retained (Figure 4 a,b). Epithelial membrane antigen (EMA) immunostaining showed ring-like and dot-like reactions in tumour cells. L1CAM was focally positive.The Ki-67 labelling index was less than 2%. Expression of p53 protein, IDH-1, and neuronal proteins such as synaptophysin and enolase was not observed.
Discussion
Ependymomas are rare neuroepithelial tumors that arise from ependymal cells lining the ventricles and the central canal of the spinal cord or cortical rests. Representing about 3% of all intracranial and spinal tumors, they account for 5-6% of all gliomas. According to the Central Brain Tumor Registry of the USA, the annual incidence of ependymomas ranges from 0.29 to 0.6 per 100,000 persons.5
These tumors typically manifest in the posterior fossa, especially in children, where they can obstruct cerebrospinal fluid flow and lead to hydrocephalus. In adults, ependymomas can also be found in the spinal cord and, less commonly, in the cerebral hemispheres, often presenting as large, cystic, and calcified extraventricular masses.6
Clinical presentations
Ependymal tumours shows bimodal age distribution showing a peak in the 0–4 year age group and second peak in the 55–59 year age group.Intracerebral ependymomas can indeed lead to a variety of symptoms based on their location and the extent of mass effect. Common presentations are related to obstructive hydrocephalus, symptoms include headache, nausea, vomiting, and altered consciousness. Other symptoms such as focal neurological deficits weakness, sensory loss, personality alteration and Seizures. Supratentorial ependymomas produce symptoms of increased intracranial pressure manifesting as headache, nausea, vomiting, aphasia, cognitive impairment, seizures etc. Early diagnosis and intervention are critical for improving patient outcomes.7
Neuroimaging in diagnosis for ependymal tumors
MRI with contrast enhancement is the modality of choice for diagnosing ependymal tumors.8 On CT imagining, supratentorial ependymoma appear as heterogenous masses due to cystic areas and calcification; hypointense to white matter with T1 MRI, hyperintense to white matter with T2 MRI. In our case showed, the right fronto-parietal lobe with hypodense areas and extensive calcifications within. W G Armington et al observed intratumoral calcification in one-third of the cases.9
Soares de Oliveira VM, et al, reported case of a supratentorial ependymoma with giant cells, extensive tumour cell vacuolization and calcification.10 These tumors are solid and cystic masses, with heterogeneous enhancement. Necrosis, calcification, and haemorrhage are variable. On imaging distinguishing these tumors from other masses is difficult and requires histopathological correlation.
Histomorphological features
Histologically, ependymomas shows varying degrees of differentiation and may exhibit features like rosettes. On gross examination, ependymoma typically present as gray-red, fleshy, relatively circumscribed mass lesion. These tumor may exhibit various features like cysts, high cellularity, papillary structures, hemorrhage, or necrosis. Ventricular location is common. While the intracranial tumors are well circumscribed.
The histopathological assessment is primarily based on hematoxylin-eosin-stained sections. On microscopic examination ependymomas are cellular tumor with circumscribed or may be infiltrative borders.The individual tumor cells are monomorphic round to oval cells with speckled chromatin. Perivascular pseudorosettes, true ependymal rosettes, lumina and fibrillar areas are present. papillary structures Rare cases cysts formation, calcification, cartilagineous metaplasia is noted.in our case there was extensive calcifications were noted.11 A Huge Calcified Supratentorial Ependymoma reported by Yangi K, et al.,12
The common pathology features for all ependymoma subtypes include perivascular pseudorosettes, ependymal rosettes. Ependymal tumours as per WHO classification grade from.1, 2, 3
Immunohistochemical features and molecular profiling has identified distinct subtypes, which can influence treatment decisions and prognostic outcomes.
Immunohistochemical features
The tumor cells showed glial fibrillary acid protein (GFAP) immunostaining, highlighting the perivascular pseudorosette cell processes. S100 cytoplasmic positivity, Epithelial membrane antigen EMA, dot-like perinuclear reactivity and negative Olig2 nuclear reactivity.Other immunostains D2-40, CD56 CD 99, keratin (CAM 5.2) focally and synaptophysin. L1CAM can be positive in some supratentorial ependymomas.13 In our case GFAP, EMA were positive immunostaining.
The 2021 WHO CNS tumor classification still recommend assigning either WHO grade 2 or grade 3 to an ependymoma, according to histopathological features.While myxopapillary ependymoma are now WHO grade 2.14 A study from Parker M et al noted that the nuclear immunoreactivity for v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) and expression of L1 cell adhesion molecule may help to identify RELA fusion-positive ependymomas.14
Molecular features
Ependymoma, NOS (not otherwise specified) is used when molecular analysis is missing. Supratentorial ependymomas are heterogeneous from clinical, molecular and morphological perspectives and classified as supratentorial ependymoma ZFTA fusion positive (ST-ZFTA), supratentorial ependymoma, YAP1 fusion positive (ST-YAP1) or supratentorial subependymoma (ST-SE). Recently, a tumor with fusion of YAP1 and MAMLD1 genes in a female infant with supratentorial ependymoma was described.14
The DNA methylation profiling has become an integral part of classifying the tumor type. Ten types of ependymal tumors based on global DNA methylation profiling are applying the new classification system. Capper D et al observed that the DNA methylation profiling has improved prediction of patients’ outcome, recurrence and overall survival.15 There is a group of neuropathology and neuro-oncology which gives recent guidelines by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) committee in 2020 have distinguished ependymal tumors according to methylome profiling.16
The posterior fossa ependymomas on the methylation profiling divides into posterior fossa group A (PFA), group B (PFB) and posterior fossa subependymoma/PF-subependymoma, which are also distinguished by levels of H3 p-K27me3.17 While spinal ependymomas on molecular profile include myxopapillary morphology or the more aggressive type of spinal ependymoma with MYCN amplification.18, 19 The differential diagnosis includes, angiocentric glioma consists of monomorphic, bipolar spindled cells with elongated nuclei and characteristic angiocentric arrangements around cortical blood vessels, forming perivascular pseudorosettes with an ependymoma-like appearance. Schwannoma shows alternating Antoni A, Antoni B areas or Verocay bodies. Rare neuroblastoma-like variant shows collagenous material, rosette-like structures surrounded by small, round, hyperchromatic Schwann cells, Schwannoma are strongly S-100 positive and GFAP negative. Other differentials are meningiomas are GFAP negative and EMA positive. Pilocytic astrocytoma of the 4th ventricle, these tumors do not have perivascular pseudorosette. Ependymomas shows variable areas of cystic or myxoid degeneration, calcifications, degenerative atypia. However extensive calcification is rarely noted. When such calcification is observed the differentials are meningioma.20 The GFAP immunoreactivity is negative in meningioma.
Treatment and prognosis
The treatment of patients with ependymomas is surgical intervention. The gross total resection is optimal. Depending on infiltration, histopathological type, metastasis, molecular study requires adjuvant chemotherapy or radiation and subsequent MRI surveillance for recurrence following resection for 5-10 years is required. Rudà, R et al observed that the chemotherapy is typically reserved for cases of advanced or recurrent ependymoma, unresectable or irradiated.21 Temozolomide has also been used in combination with lapatinib in a single-arm phase II study in patients with recurrent intracranial and spinal ependymomas.22 A multicenter retrospective study showed that the Platinum-based regimens treated with cisplatin had reported higher response rates in patients with progressive or recurrent ependymoma.23 Leeper H et al noted,supratentorial ependymomas often present a higher histological grade and have a lower survival rate despite treatment with resection and adjuvant radiation.24 Ependymomas have varying prognosis based on their age of onset, location, and histopathologic appearance and treatment risk factor.25 McGuire et al, observed higher rates of survival for spinal tumors as compared to infratentorial and supratentorial tumors.26 The new molecular classification has implications particularly in targeted therapeutics for ependymomas.
Conclusion
This study demonstrates the various ependymoma for its clinical, radioimaging, histopathological, immunohistochemical and molecular findings with recent updates. The supratentorial ependymoma with extensive intratumoral calcification is rare finding. It is important to know the biology of supratentorial ependymoma with a proper approach to integrated diagnosis technics which will help meaningful treatment for better care of patients.
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