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ORIGINAL ARTICLE
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Clinical experience and management outcome of WHO grade II pediatric intramedullary ependymomas: A descriptive study


1 Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Biostatistics and Health Informatics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission02-Jan-2021
Date of Decision27-Mar-2021
Date of Acceptance23-May-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Ved P Maurya,
Department of Neurosurgery, First Floor, C- Block (Hospital Building), Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, Uttar Pradesh.
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_2_21

 

   Abstract 

Background: Intramedullary ependymom‑a is a rare primary tumor in the pediatric population. The World Health Organization (WHO) grade II pediatric intramedullary ependymoma (PIME) is the most common in frequency, though it is a less discussed pathological grade. This study aims at sharing the clinical experience and management outcome of WHO grade II PIME from a tertiary care center. Materials and Methods: The clinico-radiological details of all histologically proven, newly diagnosed primary PIME that underwent management were collected. Recurrent lesions and other spinal cord tumors were excluded. Details of surgical intervention and follow-up visits were reviewed from the record-keeping system. The surgical nuances and outcome predictors in the form of functional grade were analyzed. The statistical data were calculated by using the appropriate statistical tests. Results: The mean age of the study population was 16.3 ± 4.0 years. The male-to-female ratio was 2:1. The pain was noticed in 14 patients (14/18 [77.8%]), and four (22.2%) patients were ambulant at the time of admission. Overall, 15 (83.3%) patients underwent total excision, and subtotal excision was achieved in three patients. The median follow-up period was 31.0 months, and the range was 2–126 months. After surgical decompression of tumor, there was a significant improvement in the modified McCormick’s grade, when median score was compared between preoperative period and the last follow-up visits (4 [2.8–4] vs. 2 [2–3], P = 0.001). There was one case of surgical mortality, with two symptomatic recurrences after surgical resection. Conclusions: The progression-free survival (PFS) and overall survival (OS) depend on early excision at better functional status. Age, gender, and vertical extension of tumor have a debatable impact on the overall outcome in PIME.


Keywords: Benign, cellular, radiotherapy, tanycytic, vascularity



How to cite this URL:
Singh Y, Maurya VP, Srivastava AK, Das KK, Bhaisora KS, Sardhara J, Verma PK, Mehrotra A, Jaiswal AK, Behari S, Mishra P, Agrawal S. Clinical experience and management outcome of WHO grade II pediatric intramedullary ependymomas: A descriptive study. J Pediatr Neurosci [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=327893





   Introduction Top


Ependymoma is the primary neoplasm of the central nervous system, and it is known to affect children and young adults. Ependymoma was considered to arise from the lining of the cerebral ventricles or the central canal of the spinal cord. The latest insight into the subject revealed that radial glial stem cells are the source of origin. The occurrence of these tumors along the spinal cord depends on age groups and histological subtypes.[1] The World Health Organization (WHO) grade II ependymomas represent the nature of benign pathology marked by their tendency to grow slowly and compress the cord matter asymmetrically rather than causing infiltrative damage, which in turn, suggests a long-standing indolent course.[2] This retrospective observational study was conducted to review the WHO grade II pediatric intramedullary ependymoma (PIME) and to determine the management outcome associated with this most common, though less published histological grade of ependymoma in the pediatric population.


   Materials and Methods Top


Inclusion criteria

This retrospective, observational study was conducted in the Department of Neurosurgery, a tertiary care referral center and the study was approved by the institutional ethics committee. We collected the clinical and radiological details of all histologically proven, newly diagnosed cases of WHO grade II PIME who underwent surgical intervention over the past 10 years, that is, from January 2010 to January 2020.

Exclusion criteria

The cases who were found to have the following were excluded:

  • Spinal ependymoma other than WHO grade II (i.e., grade I and III)


  • Nonconclusive biopsy


  • Recurrent and residual lesions


  • Methodology

    The detailed clinico-radiological, operative, and postoperative follow-up data were recorded from the hospital information and record-keeping system. Specific details included: documentation of symptom complex such as intensity of pain (using Graphic Rating Scale [GRS]), modified McCormick’s grade [Table 1], neurocutaneous stigmata and associated orthopedic deformity (if any) at the time of admission, and subsequent follow-up visits at six weeks, six months, and later on a yearly basis as per the department policy. Patients with urinary complaints at the time of admission were subjected to urodynamic studies to rule out the associated urological disorder. Patients who became symptomatic at the time of growth spurts were evaluated for associated thickened filum terminale. Those patients with neurocutaneous stigmata were evaluated for tumor of other systems to rule out the syndromic association [Table 2].
    Table 1: Modified McCormick’s scale

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    Table 2: Clinical picture with disease characteristics

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    Radiological assessment

    Patients having lesions at the cervicomedullary junction (CMJ) and cervical spine were evaluated to rule out hydrocephalus and/or associated  Chiari malformation More Details respectively. Those patients with associated deformity in the form of scoliosis, kyphosis, or any other curvature deformity underwent X-ray, computed tomography (CT) scan of the spine with the evaluation of Cobb’s angle. The spine curvature was evaluated in detail before subjecting these patients to surgery [Table 3].
    Table 3: Radiological characteristics

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    Surgical intervention

    All the included patients were subjected to standard laminectomy or laminoplasty and tumor decompression. Tumor exposure was done by performing laminectomy one level above and one level below the extent of the lesion. The tumor was approached through standard midline myelotomy; dentate ligaments were useful landmarks in identifying the dorsal median raphe in case of asymmetrical cord expansion. The extent of tumor exposure was doubled with the generous application of pial sutures in 12 out of 18 cases [Figure 1].[3] The extent of tumor resection was described as gross total resection (GTR): >95%, subtotal resection (STR): 50–95%, partial resection: 25–50%, and tumor biopsy: up to 25%, of tumor decompression. The safe surgical decompression of the tumor was expedited with the use of the following adjuncts:
    Figure 1: A, Figure showing post-durotomy symmetrically expanded cord with dilated tortuous subarachnoid vessels (blue triangles). B, Generous tumor exposure by applying pial sutures (blue arrows). C, Operative cavity after GTR of tumor.

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    1. Intraoperative neuromonitoring (IONM): Electrophysiology-guided tumor excision employed motor-evoked potential (MEP), somatosensory-evoked potential (SSEP), and electromyography (EMG) as an important modality to achieve maximal safe resection (XLTEK; protector 32 Stimulator and Acquisition [Natus® Medical Inc., Ontario, Canada]).

      A decrease in amplitude beyond 50% warns the surgeon about expected neurological damage. Recently, D-wave has been included to provide a direct quantitative measurement of the corticospinal tract independent of the muscle relaxant or the depth of anesthesia.[4],[5],[6]


    2. Intraoperative ultrasonography (IOUSG): Ultrasonography helped to estimate the tumor location, tumor depth from the cord parenchyma, relation to adjacent blood vessels, and best possible trajectory in real-time (M-Turbo Ultrasound System [Fujifilm Sonosite, Inc., Bothell, USA]). Ultrasound scanning is based on echo intensity and the depth of perception. Linear transducer probes (frequency range: 6–15 MHz) and B-mode scanning (or brightness mode) were the most commonly used settings for intramedullary tumors.[7]


    3. Cavitron ultrasonic aspirator (CUSA): This is an exceptionally useful equipment that is utilized to achieve rapid cytoreduction of tumor volume. The tumor decompression is facilitated by intact physiology and vascular integrity as close to 1mm distance from the CUSA tip. The availability of various types of CUSA tip has overcome the limitations regarding the accessibility and consistency of tumors[8] (Sonoca 300, Ultraschall-Dissektor [Soring GmbH, Quickborn Germany]). The decompression of the syrinx and cystic component helped achieve the normal cerebrospinal fluid (CSF) pathway. The vascularity and the extent of tumor served as deciding factors for the operating time and the amount of blood loss during tumor excision.


    Postoperative evaluation

    Postoperative clinical and radiological assessment was conducted six weeks after the surgery. The histological variants of this WHO grade II ependymoma were noticed from the histopathology report. A detailed examination of sensory, motor, and autonomic systems along with postoperative magnetic resonance imaging (MRI) spine was performed to look for the extent of resection or residual tumor. The subsequent clinical and radiological assessment was conducted at six months after surgery and later on every year to look for the recurrence, if any.

    Statistical analysis

    Continuous variables in the present study were presented as mean ± standard deviation/median (interquartile range), whereas categorical variables were presented in the form of frequency (%). Means were compared by using independent-samples t-test, whereas proportions were compared by using Fisher exact test. To estimate overall survival (OS), Kaplan–Meier analysis (univariate analysis) was used to compute the mean survival time whereas median survival time could not be obtained as survival proportion did not reach 50% or below. For survival analysis, patient death was considered as an event of interest whereas the Breslow test was used to compute statistical significance. Surgical excision, radiotherapy (RT) after surgery, and tumor recurrences were considered as the main independent variables. Multivariate analysis was not performed, because no variable was detected to be significant in the univariate analysis as the sample size was small. The P value < 0.05 was considered significant. Statistical package for social sciences, version 23 (SPSS-23, IBM, Chicago, USA) was used for data analysis.


       Results Top


    A total of 18 patients were recruited in this retrospective observational study. The median age at admission was 17.5 years (range: 6–20 years). Males (n = 12, 66.7%) outnumbered females (n = 6, 33.3%). In this study, two (11.1%) patients presented in their first decade whereas 16 out of 18 (88.9%) patients were older than 10 years of age. Overall, 14 patients were in the adolescent age group (10 to 19 years), whereas two patients were 20-years-old [Table 2]. The median duration of symptoms before admission was 12 months (range 2–48 months). The tumor location was noticed at the cervical (n = 11), thoracic (n = 1), cervicothoracic (n = 2), and thoracolumbar (n = 4) region. Four out of 11 cases in the cervical region had an extension in the cervicomedullary junction. The cellular variants were 10 in number, the papillary variants were four, and the clear and tanycytic variants contributed two each to the histological diagnosis of this grade II PIME.

    Associated anomaly

    Two patients were found to be a part of neurofibromatosis (NF-I) with café au lait spots along with the presence of cranial and spinal lesions reflecting the extent of the disease. A right intra-canalicular vestibular schwannoma was noticed in one patient, and thoracic schwannoma with the syndromic association was detected in another patient. Two patients were found to have scoliotic deformity, whereas one patient had mild kyphosis of the thoracic vertebrae at admission.

    Surgical outcome

    Complete tumor excision was achieved in 15 (83.3%) cases, whereas subtotal decompression was attained in three (16.7%) patients. A total of 13 patients underwent tumor decompression with IONM as a monitoring modality. The remaining patients could not undergo IONM either due to nonavailability or because it could not be performed. The MEP was dropped in eight out of 13 patients. This drop in MEP was in an attempt to achieve complete resection of the tumor. In all these patients, there was weakness during the immediate postoperative period, and these patients recovered over a period of time. The patients in whom the fall in MEP was noticed at the end of the decompression performed better, due to displaced fiber tracts (exophytic nature of the lesion), as compared with those in whom the fall was noticed relatively early (infiltrative nature of the lesion) during tumor decompression.

    The operative issues that preclude complete excision of these tumors were ill-defined tumor–spinal cord interfaces, adhesions to multiple nerve roots at the cervical as well as the lower end of the spinal cord. An increased amount of blood loss was noticed in long-segment disease as compared with the short-segment pathology, but this was not statistically significant [Table 4]. Four patients had a lesion in the transition zone, three in the cervicothoracic zone, and one in the thoracolumbar zone; these patients underwent stabilization to avoid deformity and instability [Figure 2] and [Figure 3]. Immediately after surgery, there was a drop in motor power in almost all the cases operated at our center. Two patients were noticed to have gait disability in our study population. The occurrence of posterior column dysfunction was noticed in one patient, which contributed to the gait disability. Another patient had persistent sensory-motor complaint, leading to instability in gait. The recovery to the preoperative stage or a better grade was noticed after three months and later [Table 5]. There was CSF leak and wound infection in three cases and these were managed with resuturing of the wound. There was no case with postoperative meningitis.
    Table 4: Comparative representation of short-segment vs. long-segment disease

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    Figure 2: A, T1 weighted images of MRI axial view suggests symmetrical dilatation of spinal cord. B, T2 weighted images of MRI sagittal view suggests heterogeneous lesion at the cervicothoracic junction with proximal as well as distal hyperintense cystic dilatation of the cord. C, The contrast-enhanced coronal view suggests enhancement of the lesion.

    Click here to view
    Figure 3: A, T2 weighted images of MRI sagittal view showing adequate GTR of the tumor with an adequate CSF column ventral to the cord. B, X-ray spine suggestive implants in situ extending from C5 lateral mass to D2 pedicle screw with good bony alignment.

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    Table 5: Demography and modified McCormick’s grade

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    After surgery, there was a significant reduction in pain score at six weeks as compared with preoperative pain, evaluated on GRS (Preop score: 4.0 ± 2.3, Postop score: 1.4 ± 0.9; P value = 0.001).[9] At six weeks of follow-up, there was a significant reduction in numbness as compared with preoperative status, which resulted in a better perception of sensory stimulus (P = 0.04). Adjuvant RT was administered to three patients, which comprised a dose of 55 Gray in 30 fractions over six weeks by conventional three-dimensional (3D) conformal RT. The RT was given to these three patients because of the significant amount of the residual lesion. A margin of 5mm beyond the tumor boundary was included in the clinical target volume, and RT was tolerated well by the patients. Readmission was noticed in two patients, with worsening clinical symptoms in the form of unsteadiness in gait and urinary incontinence, after 10 months in one and in another at 14 months of tumor decompression. These patients belong to the STR cohort. A second surgery was performed in both cases, and these patients made an uneventful recovery.

    Outcome predictors

    In our study, out of 18 patients, one patient (1/18, 5.6%) died during the reference follow-up time. The mean and median follow-up period was 42.1 months and 31.0 months, with a range of 2–126 months; however, the mean survival time of the patients was 119.11 months (95% confidence interval [CI] = 106, 132). The overall event-free survival time of the patients is presented in the Kaplan–Meier survival curve [Figure 4]A. The survival time of the patients undergoing GTR was compared with that of those undergoing STR. No significant difference was observed in the survival time between the two groups (P = 0.655) [Figure 4]B. Adjuvant 3D conformal RT was delivered in three patients. There was no significant difference in survival time between patients who received RT and those who did not receive RT (P = 0.627) [Figure 4]C. After STR, recurrence was observed in two patients with no mortality; however, no recurrence was noticed in those who underwent GTR with one case of mortality reported (P = 0.724) [Figure 4]D. In our study, one patient died after two months of surgery and another patient could not be contacted after the second follow-up visit at six months. There was a significant improvement in the modified McCormick’s grade when the median scores between the preoperative period and the last follow-up visits were compared (4 [2.8–4] vs. 2 [2–3], P = 0.001). Patients with a better preoperative modified McCormick’s grade (1–2) were found to perform better in the long-term follow-up [Figure 5] and [Figure 6]. Better preoperative functional grade, shorter duration of symptoms, and short segment involvement predicted better postoperative functional outcomes.
    Figure 4: Kaplan–Meier survival analysis showing survival probability in patients during the follow-up period. A, Showing survival function in terms of mortality. B, GTR vs. STR. C, Those receiving radiotherapy vs. no radiotherapy. D, Recurrence vs. no recurrence.

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    Figure 5: Follow-up MRI spine after four years of surgery, A, T2 weighted images showing a sagittal view of the follow-up case operated for D10-D11 grade II ependymoma with laminectomy defect at D9 to D12 level. The presence of central syrinx noticed from D3 to the level of conus. B, T1 weighted images showing central syrinx with no residual mass lesion. C, Coronal view after contrast administration reveals no abnormal enhancing mass or leptomeningeal enhancement.

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    Figure 6: A, Follow-up MRI spine after six years of surgery. T2 weighted images showing a sagittal view of the follow-up case operated for C3 to C6 grade II ependymoma with retained posterior segment (post-laminoplasty changes). Foci of signal changes in the form of hyperintensity noted over the operative site. B, T2 weighted images showing axial view at C4 vertebra level with signal changes in the cord parenchyma. C, CT volume rendering technique (VRT) image of the cervical spine showing laminoplasty changes with mini plates and screws in situ.

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       Discussion Top


    Primary pediatric spinal cord tumors are rare neoplasms accounting for an annual incidence of 0.9–2.6% per lakh population.[10] Among the pediatric spinal cord tumors, astrocytomas contribute to about 60–80%, whereas the remainder is attributed to ependymoma.[11] The incidence of the WHO grade II spinal cord ependymoma in the pediatric population is rare.[12]

    Intramedullary tumors of the spinal cord in the pediatric population contribute to about 4–6% of all the central nervous system malignancies.[13] The incidence of pediatric intramedullary spinal cord tumors (PIMSCT) in the present study was up to 18.5% of all the spinal cord tumors managed at our center over the past decade. The PIME contributes to about 75% of the intramedullary spinal cord tumor (IMSCT) and the WHO grade II shares about 75% of the PIME; however, the WHO grade I shares about 8.3% and grade III shares about 16.7% of the PIME. Demographic studies support greater incidence in males, with a predilection toward black and Hispanics rather than whites.[14],[15]

    Clinical presentation

    Localized pain with increasing weakness that hampers the day-to-day activity is the most common presentation of intramedullary ependymoma.[16],[17],[18] These tumors are generally intramedullary and are concentrated in the proximal portion of the spinal cord. These benign tumors have an indolent course and are slow-growing in nature.[19] Most of the IMSCTs are characterized by slow growth and they are noticed clinically after a significant size is obtained.[20] In the Indian population, the majority of children seek medical attention once they develop significant neurological deficit during the later stage of the disease process.[21]

    Despite being the most commonly affected segment, the lesions in the cervical segment have an overall better outcome as compared with those involving the thoracic segment.[22] The literature suggests a five-year PFS and OS of PIME to be 90–100%.[19] In this observational study, at the last follow-up, 14 out of 18 patients (77.8%) were ambulant and were pain-free, which suggested benign behavior and a non-infiltrative growth pattern of WHO grade II PIME.

    Pathological spectrum

    The WHO classified the central nervous system ependymoma based on the degree of anaplasia. Similar to cranial ependymoma, the WHO has categorized spinal ependymoma into three histological subtypes: grade I—myxopapillary ependymoma; grade II—ependymoma with four histological variants, namely cellular, papillary, tanycytic, and clear cells; and grade III—anaplastic ependymoma.[23] The WHO grade II ependymoma is characterized by high cellularity and rare mitotic activity. The characteristic features are perivascular pseudorosettes, positive staining for glial fibrillary acidic protein, and the occasional presence of ependymal rosettes.[21]

    A pathoanatomical review of grade II suggests that it is not only an intermediate status between grade I and III, but instead it is much more that has been explored to date.[24] The histological variants are common for cranial as well as spinal grade II ependymoma, even though there exists a wide molecular diversity manifesting as genetic and epigenetic alterations.[25],[26],[27] NF2 mutation, overexpression of neurofilament light polypeptide (NEFL), Merlin loss, and a gain of 9q are unique genetic aberrations associated with spinal ependymoma as compared with the cranial counterpart. The overexpression of NEFL is associated with better outcome and prolonged PFS.[28] In the present study, the cellular variants were 10 in number; papillary variants were four; and clear and tanycytic variants contributed two each to the histological diagnosis of this grade II PIME. Two patients who presented with recurrence of the lesion belonged to the cellular variant of grade II PIME. This suggests the genetic heterogeneity within the same histological grade, which, in turn, dictates the biological behavior of ependymomas and could be a better predictive parameter of the outcome.

    Surgical decompression

    The GTR of grade II intramedullary ependymoma has been considered as the standard of care and is associated with better PFS and OS.[29],[30],[31],[32],[33] Surgery at a better preoperative functional grade is considered to offer a better outcome. Due to scattered literature on grade II PIME, a definitive relationship between the extent of resection and PFS or OS had a less established association. The Surveillance, Epidemiology, and End Results (SEER) database was analyzed by Lin et al. during the study period of 1973 to 2008, where the descriptive data on pediatric grade II spinal cord ependymoma were studied. The median period of follow-up was 9.2 years. The STR was more likely to be subjected to RT as compared with those with GTR (P < 0.001). Females had a better survival rate as compared with the male population. The OS was not affected significantly with either the extent of resection or adjuvant RT.[12]

    Adjuncts to surgery

    Intraoperative ultrasound enhances tumor decompression with better reliability; however, a gradual learning curve avoids interpretation errors.[20],[34],[35] It provides good evidence of the residual tumor at the deeper planes of the cord. The IONM is an important adjunct that facilitates tailored resection of the tumor and it is of great help in intramedullary tumors. Other than neuroanesthetists, trained electrophysiologists and occupational therapists are the prerequisites for carrying out monitoring guided resection.[6]

    In 2006, Shimizu et al.[36] introduced the use of 5-ALA (5-aminolevulinic acid) for excising a cervical myxopapillary ependymoma. Strong fluorescence behavior was exhibited by the tumor, and fluorescence-guided resection revealed complete tumor excision. Resection of ependymoma under 5-ALA guidance is a dependable and clinically relevant surgical adjunct.[37] The GTR is an independent predictor of PFS and OS in ependymoma. The amount of blood loss in the excision of a long segment versus a short segment is higher due to obvious reasons, but this does not influence the disease progression or the outcome.

    Deformity prevention

    The study conducted by Yasuoka et al.[38] revealed that 46% of children who are younger than 15 years of age were found to have curvature anomaly in the form of kyphosis, swan-neck deformities, and scoliosis after multilevel laminectomy and decompression of intramedullary ependymoma. Osteoplastic laminoplasty is preferred over laminectomy to maintain the anatomical architecture and for preserving the posterior tension band.[39] Children with significant spinal deformity at presentation mandate aggressive spinal fusion and stabilization.[40] In the present study, four patients (4/18, 22.2%) underwent stabilization because of multilevel laminectomy as well as pathology at the transitional segment. Sun et al.[41] observed that structural deformity limits tumor decompression and affects the PFS. In the present study, structural deformity did not preclude tumor excision.

    Adjuvant therapy

    The use of RT in grade II ependymoma is a debatable issue after GTR. In the case of subtotal excision, considerable consensus exists regarding the dose and radiation to the tumor bed unless the pathology is widely disseminated.[42],[43] After GTR, the use of RT may significantly prolong the PFS for infratentorial ependymoma but not for spinal ependymoma.[44] Proton therapy (PT) is characterized by the sparing of normal tissue, and it is increasingly being considered in the management of pediatric ependymoma. Several studies favor less incidence of acute toxicity after PT as compared with conventional RT.[45],[46]

    Szathmari et al. reported a retrospective multicentric study over 10 years in patients younger than 18 years. They analyzed epidemiologic, tumor, and treatment-related data along with prognostic factors for PFS from 2000 to 2010. Among the studied variables, only the GTR had a significant influence on the PFS (P = 0.0013). RT as adjuvant therapy was beneficial to patients with GTR, but the occurrence of relapse was not prevented in those with initial STR.[47] The use of adjuvant RT increases the PFS in cases of subtotal excision but it does not affect OS. Adjuvant chemotherapy has a limited role in grade II ependymoma, and none of the patients were subjected to chemotherapy in our study. The CSF dissemination represents distant metastasis and is a poor prognostic marker. The indolent behavior of grade II ependymoma limits the role of CSF cytology. For patients undergoing STR, CSF cytology can monitor therapeutic response and is an early indicator for recurrence of the disease.[48],[49]


       Conclusion Top


    The present study emphasizes early maximal safe resection for the symptomatic patient to achieve a better outcome. Molecular and genetic makeup of the histological subtypes plays a vital role in deciding the morphology of the tumor and recurrence-free survival. Age, gender, and vertical extension of the tumor have a debatable impact on the overall outcome in PIME. A prospective clinical trial is needed to estimate the survival benefit in patients with grade II PIME undergoing GTR in reference to the new molecular classification of the CNS tumor.

    Limitations

    The mean duration of the follow-up is short. This study is focusing on a specific grade of ependymoma for the pediatric population. The results of the study could not be generalized to the broader population in view of the retrospective nature and the small sample size of the study.

    Financial support and sponsorship

    Nil.

    Conflicts of interests

    There are no conflicts of interest.



     
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        Figures

      [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
     
     
        Tables

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