Clinical, Radiological, and Pathological Features in 43 Cases of Intracranial Subependymoma

clinical article J Neurosurg 122:49–60, 2015

Clinical, radiological, and pathological features in 43 cases of intracranial subependymoma

Zhiyong Bi, MD, Xiaohui Ren, MD, Junting Zhang, MD, and Wang Jia, MD

Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Object Intracranial subependymomas are rarely reported due to their extremely low incidence. Knowledge about subependymomas is therefore poor. This study aimed to analyze the incidence and clinical, radiological, and pathological features of intracranial subependymomas. Methods Approximately 60,000 intracranial tumors were surgically treated at Beijing Tiantan Hospital between 2003 and 2013. The authors identified all cases in which patients underwent resection of an intracranial tumor that was found to be pathological examination demonstrated to be subependymoma and analyzed the data from these cases. Results Forty-three cases of pathologically confirmed, surgically treated intracranial subependymoma were identified. Thus in this patient population, subependymomas accounted for approximately 0.07% of intracranial tumors (43 of an estimated 60,000). Radiologically, 79.1% (34/43) of intracranial subependymomas were misdiagnosed as other diseases. Pathologically, 34 were confirmed as pure subependymomas, 8 were mixed with ependymoma, and 1 was mixed with astrocytoma. Thirty-five patients were followed up for 3.0 to 120 months after surgery. Three of these patients experienced tumor recurrence, and one died of tumor recurrence. Univariate analysis revealed that shorter progression-free survival (PFS) was significantly associated with poorly defined borders. The association between shorter PFS and age < 14 years was almost significant (p = 0.51), and this variable was also included in the multivariate analysis. However, multivariate analysis showed showed only poorly defined borders to be an independent prognostic factor for shorter PFS (RR 18.655, 95% CI 1.141–304.884, p = 0.040). In patients 14 years of age or older, the lesions tended to be pure subependymomas located in the unilateral supratentorial area, total removal tended to be easier, and PFS tended to be longer. In comparison, in younger patients subependymomas tended to be mixed tumors involving the bilateral infratentorial area, with a lower total removal rate and shorter PFS. Conclusions Intracranial subependymoma is a rare benign intracranial tumor with definite radiological features. Long-term survival can be expected, although poorly defined borders are an independent predictor of shorter PFS. All the features that differ between tumors in younger and older patients suggest that they might have different origins, biological behaviors, and prognoses. http://thejns.org/doi/abs/10.3171/2014.9.JNS14155 Key Words subependymoma; clinical features; radiology; pathology; survival; oncology

ntracranial subependymoma is rare, representing istics of this type of tumor, reliable preoperative diagno- only 0.51% of all central nervous system tumors, and sis remains challenging, and many intracranial subepen- the clinical symptoms are associated with the tumor dymomas are misdiagnosed as other diseases.17 Ilocation.16 It has been proposed that subependymomas To learn more about the clinical, radiological, and derive from ependymal-glial precursor cells, astrocytes pathological features of intracranial subependymomas, of the subependymal plate, or a mixture of astrocytes we retrospectively reviewed and analyzed all of the cases and ependymal cells.12,13,16 Subependymoma was first de- surgically treated and pathologically confirmed as in- scribed by Scheinker in 1945, and more than 100 cases tracranial subependymomas in Beijing Tiantan Hospital have been described since this time.1,4,6–9,11,17,18 As a result from 2003 to 2013. We report the clinical, radiological, of the sparse reporting of subependymoma cases, their and pathological features of the entire series of cases of clinical, radiological, and pathological features remain subependymoma are reported and analyze the features as- unclear. Due to the rarity and variable imaging character- sociated with longer PFS and OS.

Abbreviations CPA = cerebellopontine angle; OS = overall survival; PFS = progression-free survival; SGCA = subependymal giant cell astrocytoma; VP = ventriculoperitoneal. Submitted January 19, 2014. Accepted September 2, 2014. include when citing Published online October 31, 2014; DOI: 10.3171/2014.9.JNS14155. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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Methods mately 60,000 cases of surgically intracranial tumors that Patient Population were treated in Beijing Tiantan Hospital during the study period. The frequency of intracranial subependymoma Review of the records of Beijing Tiantan Hospital for was thus approximately 0.07%. the period from 2003 to 2013 identified 43 patients who Clinical data are summarized in Tables 1 and 2. The had undergone resection of intracranial tumors that were age at onset of symptoms or signs in the 43 patients pathologically confirmed to be subependymomas. ranged from 2 to 68 years; the mean age was 33.1 ± 18.9 years (all means are expressed ± SD). These patients in- Record of Clinical and Radiological Material cluded 22 males and 21 females. The time from onset of The clinical data and operation records of 43 cases symptoms or signs to admission ranged from 10 days to with subependymoma were retrospectively reviewed. The 20 years (median 2 months). The initial manifestations of recorded information included patient age, sex, initial the tumor were headache or intracranial hypertension in manifestation, duration of symptoms or signs, preopera- 29 patients, dizziness in 10, limb weakness in 5, epilepsy tive diagnosis, tumor size, location, CT and MRI features, in 4, memory loss in 4, ataxia in 2, tremor in 2, blurred vi- extent of resection, and surgical outcome. Tumor size was sion in 1, and an enlarged head in 1; in 3 cases, the tumors recorded according to the measurement of the maximum were incidental findings. diameter on MR images. The extent of resection was re- All 43 intracranial subependymomas were primary. In corded as gross total, subtotal, or partial according to the 34 cases (79.1%), the tumors were misdiagnosed preop- operation record and postoperative MR images. Hydro- eratively; 14 tumors (32.6%) were misdiagnosed as glio- cephalus was defined as abnormal accumulation of cere- mas, 9 (20.9%) as central neurocytomas, 8 (18.6%) with brospinal fluid in the ventricles. ependymomas, 1 (2.3%) as medulloblastoma, 1 (2.3%) as meningioma, and 1 (2.3%) as cavernous angioma. Pathological Examination Nine patients received postoperative radiotherapy, and 1 patient received postoperative chemotherapy after tu- Fresh paraffin-embedded tumor tissue was cut into mor recurrence. 5-mm sections and stained with hematoxylin and eosin. Immunohistochemical staining was used for differential diagnoses. The microscopic pathologies of 43 cases were Radiological Features of Intracranial Subependymomas reviewed by 2 independent neuropathologists according The radiological data are summarized in Table 3. The to the WHO grading system.10 Immunohistochemical lesion was located near the Monro foramen in 21 cases, staining was assessed using a semiquantitative scoring in the fourth ventricle in 7 cases, in the occipital horn system. The expression levels were based on the percent- of the lateral ventricle in 6 cases, in both the region of age of immunopositive cells (negative, < 25% of tumor the Monro foramen and the 3rd ventricle in 3 cases, in cells; positive, ≥ 25% of tumor cells). the temporal horn of the lateral ventricle in 1 case, in the fourth ventricle and the pons in 1 case, in the CPA in 1 Long-Term Follow-Up case, in the frontal lobe in 1 case, in the parietal lobe in 1 case, and in the thalamus, midbrain, and temporal lobe Among 43 patients with subependymoma, 35 were in 1 case. followed up after surgery. Postoperative complications The tumor was located on the left side in 19 cases and and progression-free and overall survival were recorded. on the right side in 13 cases; it was bilateral in 11 cases. Progression of subependymoma was defined according to Multiple lesions were revealed in only 1 case, while the radiological findings after tumor removal. Progres- single lesions were observed in 42 cases. Regarding tumor sion-free survival (PFS) was defined as the time between shape, 39 tumors were spherical, and 4 were irregular. initial surgery and tumor progression on radiology. Over- The maximum diameters of the lesions ranged from all survival (OS) was defined as the time between initial 2.0 to 12.0 cm (mean 4.4 ± 1.7 cm). surgery and death. CT images were available in 22 cases. The tumors presented as a hypodensity without calcification in 13 of Statistical Analysis these cases, a hypodensity with calcification in 2 cases, an To select parameters associated with longer PFS and isodensity without calcification in 4 cases, an isodensity OS, the log-rank test and Cox regression model were used. with calcification in 1 cases, and a hyperdensity without The chi-square test was used for the comparison of adult calcification in 2 cases. and childhood subependymomas. The statistical software MR images were available in 38 cases. The tumors SPSS 13.0 (SPSS for Windows, version 13.0, SPSS Inc.) presented as hypointense on T1-weighted images and was used. Probability values were obtained from 2-sided hyperintense on T2-weighted images in 36 cases and as tests, with statistical significance defined as p < 0.05. isointense on T1-weighted images and hyperintense on T2-weighted images in 2 cases. The tumors presented Results with spot-like enhancement in 21 cases, no enhancement in 11 cases, ring-like enhancement in 4 cases, and homo- Frequency and Clinical Features of Intracranial geneous enhancement in 1 case. According to the radio- Subependymomas logical findings, the tumor border was well defined in 37 Forty-three cases of pathologically confirmed intracra- cases and poorly defined in 3 cases. Cystic degeneration nial subependymoma were identified among the approxi- was found in 35 subependymomas, including 34 cases

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Periop Improved Improved Improved Improved Improved Death Improved Worsened Improved Worsened Improved Worsened Worsened Improved Worsened Worsened Improved Worsened Improved Worsened Worsened Improved Improved Improved Improved Worsened Improved Improved Improved Improved Improved Improved (continued) Outcomes Treatment Surgery Surgery+RT Surgery+RT Surgery+RT Surgery+NA Surgery Surgery+NA Surgery+NA Surgery Surgery Surgery Surgery+NA Surgery Surgery Surgery+RT Surgery Surgery+RT Surgery Surgery Surgery+RT Surgery Surgery+NA Surgery Surgery Surgery+NA Surgery Surgery+RT Surgery Surgery Surgery Surgery+RT Surgery

midbrain, vermis vermis

oblongata pellucidum pellucidum pellucidum pellucidum pellucidum pellucidum lobe

Site of Origin & temporal lobe ventricle ventricle wall ventricle wall Thalamus Ventricle wall Septum Ventricle wall Cerebellar Ventricle wall Medulla Pons & pontibrachium Ventricle wall Thalamus, Ventricle wall Septum Ventricle wall Parietal Pontibrachium Septum Thalamus Ventricle wall Lateral recess of 4th Pons & medulla Cerebellar Septum pellucidum & Septum Ventricle wall Septum Septum Ventricle wall Ventricle wall Ventricle wall Septum pellucidum & Ventricle wall Caudatum & thalamus

EOR STR GTR STR GTR STR GTR STR Partial GTR Partial STR GTR STR GTR GTR GTR GTR STR GTR GTR Partial STR GTR GTR GTR STR GTR GTR GTR GTR STR GTR VP No No Yes No No No Yes No No No No Yes No No No No No Yes Yes No No No No No No No No No No No No No Shunt Yes Yes No Yes Yes Yes Yes No No No No Yes No Yes Yes No Yes No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Hydrocephalus angioma

Diagnosis

neurocytoma neurocytoma neurocytoma neurocytoma neurocytoma neurocytoma neurocytoma neurocytoma

Preop Subependymoma Subependymoma Ependymoma Glioma Ependymoma Astrocytoma Ependymoma Glioma Ependymoma Glioma Central Cavernous Central Glioma Glioma Central Subependymoma Ependymoma Ependymoma Subependymoma Glioma Central Ependymoma Central Central Subependymoma Meningioma Central Glioma Glioma Astrocytoma Central 7.0 4.0 4.5 4.0 4.0 4.0 4.0 4.0 4.5 4.2 4.0 6.0 5.0 5.0 4.0 4.0 5.0 4.0 5.0 4.0 3.5 6.0 5.0 5.0 3.0 3.0 3.5 6.0 3.0 3.5 3.0 12.0 (cm) Size Rt Lt Lt Bilat Bilat Lt bilat Rt Rt Rt Bilat Lt Lt Rt Bilat Bilat Lt Lt Bbilat Lt Bilat Bilat Rt Rt Rt Lt Rt Rt Lt Rt Lt Rt Side ventricle ventricle ventricle 3rd 3rd 3rd & & & Location horn horn

horn horn

lobe lobe

foramen foramen foramen poral Monro foramen Monro foramen Monro foramen Monro 4th ventricle Monro foramen 4th ventricle CPA Monro foramen Thalamus, midbrain, & tem- Monro foramen 4th ventricle & pons Monro Parietal Temporal Monro foramen Monro foramen Occipital 4th ventricle 4th ventricle Monro 4th ventricle Monro foramen Monro foramen Monro foramen Monro foramen Occipital Monro foramen Monro foramen Monro foramen Occipital Monro foramen M 7, 8, M 5, M 2, M 5, F Sex M 47, F 27, 12, F 12, M 19, M 10, M 13, 52, F 52, 29, F 28, F 49, F 34, M 44, F 49, M 54, M 43, F 34, M 50, M 53, F 33, F 36, M 45, M 38, F 60, F 44, F 54, M 46, M 58, F linical, radiological, and pathological features of 43 cases of intracranial subependymoma 43 cases of pathological radiological, linical, and features of Age (yrs), 1. C 1. LE 1 2 3 4 6 5 7 8 9 11 17 12 13 14 15 18 10 19 16 21 31 32 24 25 27 20 23 28 B 26 22 29 30 No. Case TA

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with microcystic degeneration and 1 case with macrocystic degeneration. Periop Improved Improved Improved Improved Improved Improved Improved Improved Improved Improved Improved Outcomes Surgical Findings and Outcomes Data pertaining to surgical findings and outcomes are presented in Table 4. Intraoperative blood loss in the 43 cases ranged from 50 to 800 ml (median 200 ml). Seven- teen tumors were found to originate from the lateral wall of the lateral ventricle, 10 from the septum pellucidum Treatment with or without involvement of the lateral wall of the lat- Surgery Surgery Surgery Surgery+RT+chemo Surgery Surgery Surgery+NA Surgery Surgery Surgery Surgery eral ventricle, 5 from the brainstem, 4 from the thalamus with or without involvement of the caudate nucleus or brainstem, 3 from the cerebellar vermis, 3 from the frontal/parietal/occipital lobe, and 1 from the lateral recess of vermis

lobe

oblongata pellucidum pellucidum the fourth ventricle. Gross-total resection was achieved in

lobe 30 cases, subtotal resection in 10 cases, and partial resec-

Site of Origin tion in 3 cases. Ventricle wall Septum Septum Medulla Ventricle wall Ventricle wall Frontal Cerebellar Occipital Ventricle wall Ventricle wall Postoperative complications present at discharge included limb weakness or paralysis in 6 cases (14.0%), hydrocephalus requiring treatment with a ventriculoperi-

EOR toneal (VP) shunt in 3 cases (7.0%), cough when drink- GTR GTR GTR GTR GTR GTR GTR GTR GTR GTR GTR ing and/or hoarseness and/or dysphagia in 2 cases (4.7%), ataxia in 1 case (2.3%), aphasia in 1 case (2.3%), memory

VP loss in 1 case (2.3%), and unsmooth speech in 1 case No No No Yes No No No No No No No Shunt (2.3%). One patient died 8 days after the operation. At the time of discharge, neurological function showed improvement in 32 cases (74.4%) and worsening in 10 cases (23.3%). Yes Yes Yes Yes Yes Yes No No No No No Long-Term Follow-Up Hydrocephalus Thirty-five patients with intracranial subependymoma were followed up for 3.0–120.0 months after surgery (median 31.5 months). At the last follow-up, 3 patients had experienced tumor Diagnosis

neurocytoma progression, and the median PFS was not yet available. The 1-, 5-, and 10-year PFS rates were 97.0%, 86.2%, and

Preop 86.2%, respectively. One patient died of recurrence. The Ependyoma Central Glioma Medulloblastoma Subependymoma Glioma Glioma Subependymoma Glioma Subependymoma Subependymoma median OS was also unavailable. The 1-, 5-, and 10-year survival rates were 100.0%, 92.9%, and 92.9%, respective- 7.5 5.9 2.0 2.6 6.0 2.3 5.5 2.3 2.5 3.0 3.5 ly. Kaplan-Meier plots of PFS and OS are shown in Fig. 1. (cm) Size Pathological Features of Intracranial Subependymomas The pathological data are summarized in Table 5. Lt Lt Rt Bilat Lt Lt Lt Bilat Lt Lt Lt Side Among 43 cases of intracranial subependymoma, 34 cases were pathologically confirmed as pure subependymoma (WHO Grade I), 8 cases as subependymoma with mixed ependymoma (WHO Grade II), and 1 as subependymoma with mixed astrocytoma (WHO Grade II). horn horn horn

Immunostaining was positive for GFAP in 15 (88.2%) lobe of 17 cases, for SYN in 3 (30.0%) of 10 cases, for vi-

Location mentin in 5 (83.3%) of 6 cases, for EMA in 0 (0.0%) of Occipital Monro foramen Monro foramen 4th ventricle Monro foramen Monro foramen Frontal 4th ventricle Occipital Monro foramen Occipital 6 cases, for MBP in 1 (25.0%) of 4 cases, for S100 in 3 (75.0%) of 4 cases, for oligo2 in 3 (75.0%) of 4 cases, for NF in 0 (0.0%) of 3 cases, and for nestin in 2 (100.0%) of 2 cases. FISH was performed in 5 cases, and none har- bored 1p/19q codeletion. 8, F Sex 14, F 33, M 45, F 23, M 36, F 56, F 45, F 68, M 3.4, M 3.3, M linical, radiological, and pathological features of 43 cases of intracranial subependymoma 43 cases of pathological (continued) radiological, linical, and features of

Age (yrs), Clinical, Radiological, and Pathological Parameters 1. C 1. Associated With PFS and OS LE 41 37 42 33 35 39 40 38 36 B 34 43 No.

Case Patient age, sex, the presence of single or multiple tu- TA Chemo = chemoterapy; = cerebellopontine CPA angel; GTR = gross-total resection; NA = data not available; RT = radiotherapy; STR = subtotal resection. mors, tumor size, tumor border, the presence of hydro-

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TABLE 2. Clinical and demographic characteristics in 43 patients TABLE 2. Clinical and demographic characteristics in 43 patients with subependymoma* with subependymoma* (continued) Characteristic Value Characteristic Value Age at diagnosis (yrs) Long-term outcome (n = 35)† (continued) Mean 33.1 ± 18.9 Recurrence 3 (7.9) Range 2–68 1-yr recurrence-free rate 97.0% Sex 5-yr recurrence-free rate 86.2% M 22 (51.2) 10-yr recurrence-free rate 86.2% F 21 (48.8) Death 1 (2.6) Duration from onset to admission 1-yr survival rate 100.0% Median 2 mos 5-yr survival rate 92.9% Range 10 days–20 yrs 10-yr recurrence-free rate 92.9% Initial manifestation ICP = intracranial pressure. Headache or raised ICP 29 (67.4) * Values represent number of cases (%) unless otherwise indicated. Dizziness 10 (23.3) All means are expressed ± SD. Limb weakness 5 (11.6) † Long-term follow-up data were available in 35 patients and do not Epilepsy 4 (9.3) include the 1 patient who died shortly after surgery. Memory loss 4 (9.3) None (incidental finding) 3 (7.0) cephalus, unilateral or bilateral tumor location, extent of resection, tumor grade, pure or mixed subependymoma, Ataxia 2 (4.7) and use of radiotherapy were recorded and analyzed. Pa- Tremor 2 (4.7) rameters significantly associated with longer PFS and OS Blurred vision 1 (2.3) were identified using log-rank analysis and the Cox regres- Enlarged head 1 (2.3) sion model (Table 6). Univariate analysis revealed that only Primary or secondary poorly defined tumor borders were significantly associated Primary 43 (100.0) with shorter PFS. The association between shorter PFS and Secondary 0 (0.0) younger patient age was almost significant (p = 0.51), and for that reason it was also included in the multivariate anal- Preop diagnosis ysis. Multivariate analysis confirmed only poorly defined Glioma 14 (32.6) borders as an independent prognostic factor for PFS (RR Central neurocytoma 9 (20.9) 18.655, 95% CI 1.141–304.884, p = 0.040). No factor was Subependymoma 9 (20.9) revealed to be an independent predictor of OS. Ependymoma 8 (18.6) Medulloblastoma 1 (2.3) Comparison of Cases in Children Versus Patients 14 Years or Older Meningioma 1 (2.3) Cavernous angioma 1 (2.3) Stratification of the cases by patient age (< 14 years vs ≥ 14 years) showed many differences (Table 7). Most RT (96.8%) of the tumors in the patients 14 years or older were Yes 9 (20.9) located in the supratentorial area, whereas most (66.7%) No 27 (62.8) of those in patients younger than 14 years were located NA 7 (16.3) in the infratentorial area (p < 0.001). In the older patient Chemo group, most subependymomas (87.1%) were unilateral, Yes 1 (2.3) whereas most in the younger patient group (58.3%) were bilateral (p = 0.008). Gross-total resection was achieved No 35 (81.4) in 80.6% of patients in the older group and 41.7% of pa- NA 7 (16.3) tients in the younger group (p = 0.033). Pathologically, Long-term outcome (n = 35)† 87.1% of the tumors in patients 14 years of age or older PFS (mos) were pure subependymomas, compared with 58.3% in Median NA younger patients; the difference was marginally signifi- Range 3.0–120.0 cant (p = 0.097). Moreover, the PFS for older patients was OS (mos) longer than that for those under 14 years (p = 0.051). Median NA Range 3.0–120.0 Illustrative Cases Case 21 (continued) A 33-year-old woman was admitted to our hospital with a radiological diagnosis of subependymoma in the left lateral and third ventricles. She complained of inter-

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TABLE 3. Radiological characteristics of 43 subependymomas TABLE 3. Radiological characteristics of 43 subependymomas (continued) Characteristic No. (%) Characteristic No. (%) Location Near the Monro foramen 21 (48.8) Preop hydrocephalus 4th ventricle 7 (16.3) Yes 28 (65.1) Occipital horn of lateral ventricle 6 (14.0) No 15 (34.9) Near the Monro foramen & 3rd ventricle 3 (7.0) VP shunt 6 (14.0) Temporal horn of lateral ventricle 1 (2.3) Preop 3 (7.0) 4th ventricle & pons 1 (2.3) Postop 3 (7.0) CPA 1 (2.3) Frontal lobe 1 (2.3) mittent headache for 1 year. Neurological examination Parietal lobe 1 (2.3) revealed no positive signs. The lesion showed a hypoden- Thalamus, midbrain, & temporal lobe 1 (2.3) sity adjacent to the Monro foramen on CT (Fig. 2A and Side B) and long T1 and long T2 signals with microcystic de- Lt 19 (44.2) generation and without enhancement on MR images (Fig. Rt 13 (30.2) 2C–H). The patient underwent a left frontal transcallo- Bilat 11 (25.6) sal approach, and gross-total resection of the tumor was Single or multiple tumor(s) TABLE 4. Surgical findings and outcomes in 43 patients with Single 42 (97.7) subependymoma* Multiple 1 (2.3) Shape of tumor Characteristic Value Spherical 39 (90.7) Intraop blood loss (ml) Irregular 4 (9.3) Median 200 Max tumor diameter (cm) Range 50–800 Mean 4.4 ± 1.7 Site of tumor origin Range 2.0–12.0 Lateral wall of lateral ventricle 17 (39.5) CT density Septum pellucidum w/ or w/o lateral wall 10 (23.3) Hypodensity w/o calcification 13 (30.2) Brainstem 5 (11.6) Hypodensity w/ calcification 2 (4.7) Thalamus w/ or w/o involvement of caudate 4 (9.3) Isodensity w/o calcification 4 (9.3) nucleus or brainstem Isodensity w/ calcification 1 (2.3) Cerebellar vermis 3 (7.0) Hyperdensity w/o calcification 2 (4.7) Frontal, parietal, or occipital lobe 3 (7.0) NA 21 (48.8) Lateral recess of 4th ventricle 1 (2.3) T1 & T2 signals Extent of resection Hypointense T1 & hyperintense T2 36 (83.7) Gross total 30 (69.7) Isointense T1 & hyperintense T2 2 (4.7) Subtotal 10 (23.3) NA 5 (11.6) Partial 3 (7.0) Enhancement Surgical duration (hrs) Spot-like enhancement 21 (50.0) Median 4.0 No enhancement 11 (25.6) Range 1.7–10.0 Ring-like enhancement 4 (38.5) Periop outcome Homogeneous enhancement 1 Improved 32 (74.4) NA 6 (11.6) Worsened 10 (23.3) Tumor border Death 1 (2.3) Well defined 37 (86.0) Postop complications at discharge Poorly defined 3 (7.0) Limb weakness/paralysis 6 (14.0) NA 3 (7.0) Hydrocephalus requiring VP shunt 3 (7.0) Texture Cough when drinking/hoarseness/dysphygia 2 (4.7) Microcystic 34 (79.1) Ataxia 1 (2.3) Macrocystic 1 (2.3) Aphasia 1 (2.3) Homogeneous 1 (2.3) Memory loss 1 (2.3) NA 7 (16.3) Unsmooth speech 1 (2.3) (continued) * Values represent number of cases unless otherwise indicated. 54 J Neurosurg Volume 122 • January 2015

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TABLE 5. Pathological characteristics of 43 subependymomas* Characteristic Value (%) Pure subependymoma 34 (79.1) Subependymoma+ependymoma 8 (18.6) Subependymoma+astrocytoma 1 (2.3) GFAP + 15 (88.2) − 2 (11.8) SYN + 3 (30.0) − 7 (70.0) Vimentin + 5 (83.3) − 1 (16.7) EMA + 0 (0.0) − 6 (100.0) FIG. 1. Kaplan-Meier plots of PFS and OS for 43 patients with intracranial subependymoma. Figure is available in color online only. MBP + 1 (25.0) achieved (Fig. 2I–K). During the operation, the tumor − 3 (75.0) was found to be a gray-white mass in the left lateral and S100 third ventricles. Postoperative pathological examination + 3 (75.0) confirmed the diagnosis of subependymoma (Fig. 2O). The patient was discharged 9 days after surgery without − 1 (25.0) any neurological deterioration. She was followed up for 3 Oligo2 years, and no recurrence was found (Fig. 2L–N). + 3 (75.0) − 1 (25.0) Case 36 NF A 3-year-old child was admitted to our hospital with + 0 (0.0) a radiological diagnosis of a mass occupying the fourth − 3 (100.0) ventricle and secondary hydrocephalus. He was reported Nestin to have been suffering from nausea for 1.5 months and sleepiness for 1 month. Neurological examination revealed + 2 (100.0) papillary edema. CT revealed a hyperdensity in the fourth − 0 (0.0) ventricle (Fig. 3A). MR images revealed a lesion with long 1p/19q codeletion T1 and long T2 signals as well as spot-like enhancement Yes 0 (0.0) (Fig. 3B–G). A VP shunt was placed, and 7 days later, sur- No 5 (100.0) gery was performed via a posterior median approach with the intention of total tumor removal (Fig. 3H–J). During * Not all tumors were evaluated for these parameters. All data avail- the operation, the tumor was found to be a gray-red soft able were analyzed. mass with well-defined borders. Postoperative pathology revealed the diagnosis of a subependymoma with increased system tumor that is often misdiagnosed as other diseases. cellularity (WHO Grade I and II) (Fig. 3K). The patient To date, few series of intracranial subependymoma have was discharged 8 days after surgery without any other been reported due to its extremely low incidence. Approxi- treatment. Seven months later, the patient was readmitted mately 60,000 patients with intracranial tumors were sur- to our hospital with recurrent headache. Radiological ex- gically treated in our hospital from 2003 to 2013. Among amination revealed a recurrent mass in the fourth ventricle them, 43 patients were found to have pathologically con- (Fig. 4A–F). A second operation was performed, and gross- firmed intracranial subependymoma. To the best of our total resection of the recurrent tumor was achieved (Fig. knowledge, this is the second largest series of intracranial 4G–K). Pathological examination resulted in the diagnosis subependymoma from a single neurosurgical center. of anaplastic ependymoma (Fig. 4L). After the operation, the patient underwent radiotherapy and chemotherapy. At Lower Incidence of Intracranial Subependymoma and Its the last follow-up 21 months after the primary surgery, the Relationship With Ependymomas patient was still alive. The frequency of subependymoma in our hospital was lower than previously reported. A 0.7% incidence of sub- Discussion ependymoma was previously reported among 1000 pa- Intracranial subependymoma is a rare central nervous tients with pathologically proven intracranial neoplasms,

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TABLE 6. Results of log-rank analyses of parameters associated with PFS and OS PFS OS Parameters χ2 p Value χ2 p Value Age >14 yrs* 3.798 0.051 0.400 0.527 Sex 0.110 0.740 0.556 0.456 Single or multiple tumors 0.153 0.696 0.077 0.782 Tumor size >4.0 cm 0.540 0.462 1.333 0.248 Tumor border* 8.120 0.004 0.077 0.782 Hydrocephalus 1.097 0.295 1.000 0.317 Side 2.232 0.135 1.800 0.180 Extent of resection 1.303 0.254 1.333 0.248 Tumor grade 0.450 0.503 0.167 0.683 Mixed tumor type 0.450 0.503 0.167 0.683 RT 0.000 1.000 1.333 0.248 * Included in multivariate analysis. and an incidence of 0.4% among 1000 asymptomatic pa- subependymal glial precursor cells.3,16,17 Ependymal glial tients has been reported based on autopsy findings.13 In precursor cells are bipotential cells, with the ability to dif- our center, the estimated incidence of intracranial subep- ferentiate into either an ependymal cell or an astrocyte. endymoma was 0.07%. Among 43 subependymoma cases, we found 8 cases with Subependymoma appears most likely to arise from mixed ependymoma, and 1 with mixed astrocytoma. Our finding supports the bipotential hypothesis of ependymal TABLE 7. Comparison of features of cases stratified by patient glial precursor cells. age* Most subependymomas are benign with a low recur- Age Group rence rate. However, a few progress as anaplastic epen- Characteristic >14 yrs ≤14 yrs p Value dymoma. Recurrence was seen in 3 of our 43 patients, including 1 with recurrent subependymoma, 1 with ana- No. of cases 31 12 plastic ependymoma, and 1 with an unavailable patho- Sex logical diagnosis. M 14 (45.2) 8 (66.7) 0.206 F 17 (54.8) 4 (33.3) Clinical-Radiological Differential Diagnoses for Tumor location Intracranial Subependymomas Supratentorial 30 (96.8) 4 (33.3) <0.001 According to the location in the ventricular system and Subtentorial 1 (3.2) 8 (66.7) the unique radiological features of intracranial subependymomas, it is not difficult to distinguish them from other Sides affected tumors. According to our analysis, 39 (90.7%) of 43 cases Unilat 27 (87.1) 5 (41.7) 0.008 were located in the ventricular system. Radiologically, most Bilat 4 (12.9) 7 (58.3) present with hypodensity without calcification on CT and Preop hydrocephalus long T1 and T2 signals with no or mild enhancement on Yes 22 (71.0) 6 (50.0) 0.349 MR images. The most characteristic MR feature of intra- No 9 (29.0) 6 (50.0) cranial subependymoma is microcysts within the tumors. Intracranial subependymomas should be differentiated Postop hydrocephalus from other intracranial tumors, including ependymomas, Yes 3 (9.7) 0 (0.0) 0.548 medulloblastomas, astrocytomas, central neurocytomas, No 28 (90.3) 12 (100.0) and meningiomas. Extent of resection For subependymomas in the area of the Monro fora- Gross total 25 (80.6) 5 (41.7) 0.033 men, central neurocytoma, glioma, and ependymoma Subtotal or partial 6 (19.4) 7 (58.3) should be included in the differential diagnosis. Neurocy- tomas present with isodensity or hyperdensity with mild Pathology to moderate enhancement on CT scan.15 Spicules identi- Pure subependymoma 27 (87.1) 7 (58.3) 0.097 fied at the tumor periphery interfacing with the lateral Mixed subependymoma 4 (12.9) 5 (41.7) ventricle walls result in a scalloping appearance, contrib- Long-term outcome uting greatly to the specificity and accuracy of the diagno- PFS (mos) 0.051 sis.14 Subependymal giant cell astrocytomas (SGCAs) are OS (mos) 0.527 a common manifestation of tuberous sclerosis. SGCAs present as areas of hypodensity with calcification on CT. * Values represent numbers of cases (%) unless otherwise indicated. After injection of a contrast agent, they show mild to

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FIG. 2. Case 21. Preoperative CT (A and B) revealed a hypodensity adjacent to the Monro foramen. On preoperative MRI (C–H), the lesion showed long T1 and long T2 signals with microcystic degeneration and without enhancement. (C and E, T1-weighted images without contrast; D, T2-weighted image; F–H, T1-weighted images with contrast.) Postoperative T1-weighted MRI with contrast (I–K) confirmed total removal of the tumor. Pathological examination (O) revealed the diagnosis of subependymoma. Original magnification ×100, H & E. MR images obtained 3 years after surgery showed no recurrence (L–N, T1-weighted MR images). Figure is available in color online only. moderate enhancement.15 Most ependymomas have a cys- in the differential diagnosis. In adults, most medulloblasto- tic component, and MR contrast enhancement has been mas present as areas of hyperdensity with mild to moderate reported to show an enhancing nodule within the wall of enhancement on CT and show a low-density area consistent a cyst, heterogeneous enhancement of cystic and solid le- with cystic and necrotic degeneration. In children, the mass sions, and homogeneous enhancement of solid lesions.5 has been reported to present as an area of hyperdensity with For subependymomas in the fourth ventricle, medul- markedly homogeneous enhancement and to show no cys- loblastoma and low-grade astrocytoma should be included tic or necrotic degeneration.2 Most low-grade astrocytomas

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FIG. 3. Case 36: first operation. Preoperative CT (A) revealed a hyperdensity in the fourth ventricle. MR images (B–G) revealed a lesion with long T1 and long T2 signals as well as spot enhancement. (B and D, T1-weighted image without contrast; C, T2- weighted image; E–G, T1-weighted image with contrast.) Postoperative T1-weighted MRI with contrast (H–J) revealed gross-total resection of the tumor. Pathological examination (K) revealed the diagnosis of subependymoma. Original magnification ×100, H & E. Figure is available in color online only. present with long T1 and long T2 signals on MR images ventricle. Preoperative hydrocephalus was resolved by tu- and no or mild enhancement, similar to subependymomas. mor removal in 24 (85.6%) of 28 cases. The microcystic signal within the tumor is typically indica- Fifteen patients did not present with hydrocephalus tive of subependymoma instead of astrocytoma. preoperatively; 2 of these patients experienced acute hy- Subependymomas within the parenchyma are very dif- drocephalus after tumor removal and required VP shunt ficult to differentiate from gliomas. In 3 of our cases, pa- placement. Both patients were adults with a tumor located renchymal subependymoma were initially misdiagnosed near the Monro foramen or in the occipital horn. The fre- as gliomas because there were not enough features for quency of acute postoperative hydrocephalus was 13.3% differentiation. (2 of 15 cases). Of the 9 patients with a tumor in the posterior fossa, 7 Hydrocephalus were complicated by hydrocephalus. In these cases, pre- Twenty-eight patients experienced hydrocephalus preoperative VP shunting was recommended to avoid acute operatively, and 3 (10.7%) of them were treated with VP cerebellar tonsillar hernia. For the 34 patients with a su- shunting before tumor removal and 1 (3.6%) was treated pratentorial tumor in our series, however, ventriculo-peri- with VP shunting after tumor removal. All 3 patients who toneal shunting was not performed until acute postopera- were treated with VP shunts preoperatively were children tive hydrocephalus occurred. with a tumor in the fourth ventricle. The patient who had a VP shunt placed postoperatively was an adult with a Radiotherapy, Recurrence, and Survival tumor located near the Monro foramen and in the third Twelve patients were treated with postoperative radio-

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FIG. 4. Case 36: second operation. The patient was readmitted to our hospital for recurrent headache 7 months after the first operation. Radiological examination revealed a recurrent mass in the fourth ventricle (A–F). (A and C, T1-weighted images without contrast; B, T2-weighted image; D–F, T1-weighted image with contrast.) Postoperative MRI showed total removal of the recurrent tumor (G–K). (G, T1-weighted image without contrast; H, T2-weighted image; I–K, T1-weighted image with contrast.) Pathological examination revealed the diagnosis of anaplastic ependymoma (L). Original magnification ×100, H & E. Figure is available in color online only. therapy. Although radiotherapy did not show a significant rate and shorter PFS. All of the above differences suggest association with longer survival, it was recommended for that the tumor origins, biological behavior, and progno- patients who had subtotal or partial resection of their tu- ses of subependymomas might differ between adults and mors and for those with mixed tumor types. children. Kaplan-Meier plots of PFS and OS are shown in Fig. 1. Subependymoma is a benign tumor, and long-term sur- Clinical, Radiological, and Pathological Parameters vival can be expected of these patients. Associated With Prognosis Comparison of Cases in Children Versus Patients 14 Years To examine associations with PFS and OS in patients or Older with surgically treated subependymoma, we analyzed There were many differences with respect to tumor clinical, radiological and pathological parameters using location, sides, removal degree, pathology, and survival the log-rank test and Cox regression model (Table 6). when the patient group was divided based on age (Table Poorly defined borders were significantly associated with 7). In patients 14 years old or older, these tumors tended worse prognosis, and the association between younger age to be pure subependymomas located in the unilateral su- and shorter PFS almost reached significance. Multivariate pratentorial area and total removal tends to be easy and analysis revealed only poorly defined borders to be an in- PFS tends to be longer. By contrast, in younger patients dependent prognostic factor for shorter PFS (RR 18.655, subependymomas tended to be mixed tumors involving 95% CI 1.141–304.884, p = 0.040). No factor was revealed the bilateral infratentorial area, with a lower total removal to be an independent predictor of OS.

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Study Limitations Clinicopathological study of seven cases of symptomatic su- This was a retrospective review of surgically treated pratentorial subependymoma. J Neurooncol 61:57– 67, 2003 9. Jain A, Amin AG, Jain P, Burger P, Jallo GI, Lim M, et al: cases of a rare intracranial tumor. This series of cases in- Subependymoma: clinical features and surgical outcomes. cluded a small patient group without any control group. Neurol Res 34:677–684, 2012 Typical biases exist, and the statistical analysis is limited, 10. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, given the small number of cases and the retrospective na- Jouvet A, et al: The 2007 WHO classification of tumours of ture of the series. There is concern that correlation may the central nervous system. Acta Neuropathol 114:97–109, be an artifact of the small group size and lack of controls. 2007 Therefore, other series of intracranial subependymomas 11. Maiuri F, Gangemi M, Iaconetta G, Signorelli F, Del Basso were analyzed in the discussion, fortifying our observa- De Caro M: Symptomatic subependymomas of the lateral ventricles. Report of eight cases. Clin Neurol Neurosurg tion with similar results. 99:17–22, 1997 12. Matsumura A, Ahyai A, Hori A: Symptomatic subependymo- Conclusions ma with nuclear polymorphism. Neurosurg Rev 10:291–293, 1987 Intracranial subependymoma is a rare benign intracra- 13. Matsumura A, Ahyai A, Hori A, Schaake T: Intracerebral nial tumor with definite radiological features. Long-term subependymomas. Clinical and neuropathological analyses survival can be expected, although poorly defined borders with special reference to the possible existence of a less be- are an independent prognostic factor for shorter PFS. The nign variant. Acta Neurochir (Wien) 96:15–25, 1989 different features between features in cases involving 14. Niiro T, Tokimura H, Hanaya R, Hirano H, Fukukura Y, patients older or younger than 14 years suggest that they Sugiyma K, et al: MRI findings in patients with central neurocytomas with special reference to differential diagnosis might have different tumor origins, biological behaviors, from other ventricular tumours near the foramen of Monro. J and prognoses. Clin Neurosci 19:681–686, 2012 15. Nishio S, Morioka T, Suzuki S, Fukui M: Tumours around References the foramen of Monro: clinical and neuroimaging features and their differential diagnosis. J Clin Neurosci 9:137–141,

1. Artico M, Bardella L, Ciappetta P, Raco A: Surgical treat- 2002 ment of subependymomas of the central nervous system. Re- 16. Ragel BT, Osborn AG, Whang K, Townsend JJ, Jensen RL, port of 8 cases and review of the literature. Acta Neurochir Couldwell WT: Subependymomas: an analysis of clinical and (Wien) 98:25–31, 1989 imaging features. Neurosurgery 58:881–890, 2006

2. Bourgouin PM, Tampieri D, Grahovac SZ, Léger C, Del Car- 17. Rushing EJ, Cooper PB, Quezado M, Begnami M, Crespo pio R, Melançon D: CT and MR imaging findings in adults A, Smirniotopoulos JG, et al: Subependymoma revisited: with cerebellar medulloblastoma: comparison with findings clinicopathological evaluation of 83 cases. J Neurooncol in children. AJR Am J Roentgenol 159:609–612, 1992 85:297–305, 2007

3. Fu YS, Chen AT, Kay S, Young H: Is subependymoma (sub- 18. Sceinker IM: Subependymoma: a newly recognized tumor of ependymal glomerate astrocytoma) an astrocytoma or epen- subependymal derivation. J Neurosurg 2:232–240, 1945 dymoma? A comparative ultrastructural and tissue culture study. Cancer 34:1992–2008, 1974 4. Fujisawa H, Hasegawa M, Ueno M: Clinical features and Author Contributions management of five patients with supratentorial subependymoma. J Clin Neurosci 17:201–204, 2010 Conception and design: Jia, Bi, Ren. Acquisition of data: Jia, Bi, 5. Furie DM, Provenzale JM: Supratentorial ependymomas and Ren. Analysis and interpretation of data: Jia, Bi, Ren. Drafting subependymomas: CT and MR appearance. J Comput As- the article: Bi, Ren. Critically revising the article: all authors. sist Tomogr 19:518–526, 1995 Reviewed submitted version of manuscript: all authors. Approved 6. Hou Z, Wu Z, Zhang J, Zhang L, Tian R, Liu B, et al: Clini- the final version of the manuscript on behalf of all authors: Jia. cal features and management of intracranial subependymo- Statistical analysis: Bi, Ren. Administrative/technical/material mas in children. J Clin Neurosci 20:84–88, 2013 support: Jia, Zhang. Study supervision: Jia, Zhang. 7. Hou Z, Wu Z, Zhang J, Zhang L, Tian R, Liu B, et al: Lateral ventricular subependymomas: an analysis of the clinical Correspondence features of 27 adult cases at a single institute. Neurol India Wang Jia, Neurosurgery, Beijing Tiantan Hospital, Capital 60:379–384, 2012 Medical University, Tiantan Xili No. 6, Beijing 100050, China. 8. Im SH, Paek SH, Choi YL, Chi JG, Kim DG, Jung HW, et al: email: [email protected].

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