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

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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.

ABBREVIATIONSCPA = cerebellopontine angle; OS = overall survival; PFS = progression-free survival; SGCA = subependymal giant cell astrocytoma; VP = ventriculoperitoneal.

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.

Intracranial subependymoma is rare, representing only 0.51% of all central nervous system tumors, and the clinical symptoms are associated with the tumor location.16 It has been proposed that subependymomas derive from ependymal-glial precursor cells, astrocytes of the subependymal plate, or a mixture of astrocytes and ependymal cells.12,13,16 Subependymoma was first described by Scheinker in 1945, and more than 100 cases have been described since this time.1,4,6–9,11,17,18 As a result of the sparse reporting of subependymoma cases, their clinical, radiological, and pathological features remain unclear. Due to the rarity and variable imaging characteristics of this type of tumor, reliable preoperative diagnosis remains challenging, and many intracranial subependymomas are misdiagnosed as other diseases.17

To learn more about the clinical, radiological, and pathological features of intracranial subependymomas, we retrospectively reviewed and analyzed all of the cases surgically treated and pathologically confirmed as intracranial subependymomas in Beijing Tiantan Hospital from 2003 to 2013. We report the clinical, radiological, and pathological features of the entire series of cases of subependymoma are reported and analyze the features associated with longer PFS and OS.

Methods

Patient Population

Review of the records of Beijing Tiantan Hospital for the period from 2003 to 2013 identified 43 patients who had undergone resection of intracranial tumors that were pathologically confirmed to be subependymomas.

Record of Clinical and Radiological Material

The clinical data and operation records of 43 cases with subependymoma were retrospectively reviewed. The recorded information included patient age, sex, initial manifestation, duration of symptoms or signs, preoperative diagnosis, tumor size, location, CT and MRI features, extent of resection, and surgical outcome. Tumor size was recorded according to the measurement of the maximum diameter on MR images. The extent of resection was recorded as gross total, subtotal, or partial according to the operation record and postoperative MR images. Hydrocephalus was defined as abnormal accumulation of cerebrospinal fluid in the ventricles.

Pathological Examination

Fresh paraffin-embedded tumor tissue was cut into 5-μm sections and stained with hematoxylin and eosin. Immunohistochemical staining was used for differential diagnoses. The microscopic pathologies of 43 cases were reviewed by 2 independent neuropathologists according to the WHO grading system.10 Immunohistochemical staining was assessed using a semiquantitative scoring system. The expression levels were based on the percentage of immunopositive cells (negative, < 25% of tumor cells; positive, ≥ 25% of tumor cells).

Long-Term Follow-Up

Among 43 patients with subependymoma, 35 were followed up after surgery. Postoperative complications and progression-free and overall survival were recorded. Progression of subependymoma was defined according to the radiological findings after tumor removal. Progression-free survival (PFS) was defined as the time between initial surgery and tumor progression on radiology. Overall survival (OS) was defined as the time between initial surgery and death.

Statistical Analysis

To select parameters associated with longer PFS and OS, the log-rank test and Cox regression model were used. The chi-square test was used for the comparison of adult and childhood subependymomas. The statistical software SPSS 13.0 (SPSS for Windows, version 13.0, SPSS Inc.) was used. Probability values were obtained from 2-sided tests, with statistical significance defined as p < 0.05.

Results

Frequency and Clinical Features of Intracranial Subependymomas

Forty-three cases of pathologically confirmed intracranial subependymoma were identified among the approximately 60,000 cases of surgically intracranial tumors that were treated in Beijing Tiantan Hospital during the study period. The frequency of intracranial subependymoma was thus approximately 0.07%.

Clinical data are summarized in Tables 1 and 2. The age at onset of symptoms or signs in the 43 patients ranged from 2 to 68 years; the mean age was 33.1 ± 18.9 years (all means are expressed ± SD). These patients included 22 males and 21 females. The time from onset of symptoms or signs to admission ranged from 10 days to 20 years (median 2 months). The initial manifestations of the tumor were headache or intracranial hypertension in 29 patients, dizziness in 10, limb weakness in 5, epilepsy in 4, memory loss in 4, ataxia in 2, tremor in 2, blurred vision in 1, and an enlarged head in 1; in 3 cases, the tumors were incidental findings.

TABLE 1

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

Case No.Age (yrs), SexLocationSideSize (cm)Preop DiagnosisHydrocephalusVP ShuntEORSite of OriginTreatmentPeriop Outcomes
134, MMonro foramenLt5.0SubependymomaYesNoGTRVentricle wallSurgery+RTImproved
227, FMonro foramenBilat4.0EpendymomaNoYesSTRSeptum pellucidumSurgery+RTImproved
344, FMonro foramen & 3rd ventricleLt6.0GliomaYesNoGTRVentricle wallSurgery+RTImproved
48, M4th ventricleBilat5.0AstrocytomaYesNoSTRCerebellar vermisSurgery+NAImproved
57, MCPARt4.0GliomaNoNoPartialPons & pontibrachiumSurgery+NAWorsened
654, MMonro foramenLt4.5EpendymomaYesNoGTRVentricle wallSurgeryDeath
710, M4th ventriclebilat4.0EpendymomaYesYesSTRMedulla oblongataSurgery+NAImproved
829, FMonro foramenRt4.0EpendymomaNoNoGTRVentricle wallSurgeryImproved
912, FThalamus, midbrain, & temporal lobeRt5.0GliomaNoNoPartialThalamus, midbrain, & temporal lobeSurgeryWorsened
1034, MMonro foramenBilat7.0Central neurocytomaYesNoGTRSeptum pellucidumSurgery+NAWorsened
1152, FMonro foramen & 3rd ventricleLt4.0Central neurocytomaYesYesGTRVentricle wallSurgeryWorsened
125, MParietal lobeLt12.0GliomaNoNoSTRParietal lobeSurgeryImproved
1336, MTemporal hornRt4.0Cavernous angiomaNoNoSTRVentricle wallSurgeryImproved
1419, M4th ventricle & ponsBilat3.5GliomaYesNoGTRPontibrachiumSurgery+RTWorsened
1543, FMonro foramenBilat4.5Central neurocytomaNoNoGTRSeptum pellucidumSurgeryWorsened
1653, FMonro foramenLt4.2SubependymomaYesNoGTRThalamusSurgery+RTImproved
1738, FOccipital hornLt4.0EpendymomaNoYesSTRVentricle wallSurgeryWorsened
185, F4th ventricleBbilat6.0EpendymomaYesYesGTRLateral recess of 4th ventricleSurgeryImproved
1913, M4th ventricleBilat5.0EpendymomaYesNoPartialPons & medullaSurgery+RTWorsened
202, M4th ventricleBilat4.0GliomaYesNoSTRCerebellar vermisSurgeryWorsened
2133, FMonro foramen & 3rd ventricleLt5.0SubependymomaYesNoGTRSeptum pellucidum & ventricle wallSurgery+NAImproved
2250, MMonro foramenRt4.0Central neurocytomaYesNoGTRSeptum pellucidumSurgeryImproved
2349, FMonro foramenRt3.0Central neurocytomaYesNoGTRVentricle wallSurgeryImproved
2445, MMonro foramenRt4.0Central neurocytomaYesNoGTRSeptum pellucidumSurgery+NAImproved
2560, FMonro foramenLt3.0SubependymomaYesNoSTRSeptum pellucidumSurgeryWorsened
2654, MOccipital hornRt3.5MeningiomaNoNoGTRVentricle wallSurgery+RTImproved
2744, FMonro foramenRt4.0Central neurocytomaYesNoGTRVentricle wallSurgeryImproved
2847, MMonro foramenLt3.0GliomaYesNoGTRVentricle wallSurgeryImproved
2949, MMonro foramenRt3.5GliomaYesNoGTRSeptum pellucidum & ventricle wallSurgeryImproved
3046, MOccipital hornLt6.0AstrocytomaNoNoSTRVentricle wallSurgery+RTImproved
3158, FMonro foramenRt3.0Central neurocytomaYesNoGTRCaudatum & thalamusSurgeryImproved
3228, FMonro foramenRt5.0SubependymomaYesNoSTRThalamusSurgeryImproved
3333, MOccipital hornLt5.9EpendyomaYesNoGTRVentricle wallSurgeryImproved
3436, FMonro foramenLt2.0Central neurocytomaYesNoGTRSeptum pellucidumSurgeryImproved
3568, MMonro foramenRt2.6GliomaYesNoGTRSeptum pellucidumSurgeryImproved
363.4, M4th ventricleBilat6.0MedulloblastomaYesYesGTRMedulla oblongataSurgery+RT+chemoImproved
3745, FMonro foramenLt2.3SubependymomaYesNoGTRVentricle wallSurgeryImproved
3856, FMonro foramenLt5.5GliomaYesNoGTRVentricle wallSurgeryImproved
393.3, MFrontal lobeLt2.3GliomaNoNoGTRFrontal lobeSurgery+NAImproved
408, F4th ventricleBilat2.5SubependymomaNoNoGTRCerebellar vermisSurgeryImproved
4123, MOccipital hornLt7.5GliomaNoNoGTROccipital lobeSurgeryImproved
4245, FMonro foramenLt3.0SubependymomaNoNoGTRVentricle wallSurgeryImproved
4314, FOccipital hornLt3.5SubependymomaNoNoGTRVentricle wallSurgeryImproved

Chemo = chemoterapy; CPA = cerebellopontine angel; GTR = gross-total resection; NA = data not available; RT = radiotherapy; STR = subtotal resection.

TABLE 2

Clinical and demographic characteristics in 43 patients with subependymoma*

CharacteristicValue
Age at diagnosis (yrs)
 Mean33.1 ± 18.9
 Range2–68
Sex
 M22 (51.2)
 F21 (48.8)
Duration from onset to admission
 Median2 mos
 Range10 days–20 yrs
Initial manifestation
 Headache or raised ICP29 (67.4)
 Dizziness10 (23.3)
 Limb weakness5 (11.6)
 Epilepsy4 (9.3)
 Memory loss4 (9.3)
 None (incidental finding)3 (7.0)
 Ataxia2 (4.7)
 Tremor2 (4.7)
 Blurred vision1 (2.3)
 Enlarged head1 (2.3)
Primary or secondary
 Primary43 (100.0)
 Secondary0 (0.0)
Preop diagnosis
 Glioma14 (32.6)
 Central neurocytoma9 (20.9)
 Subependymoma9 (20.9)
 Ependymoma8 (18.6)
 Medulloblastoma1 (2.3)
 Meningioma1 (2.3)
 Cavernous angioma1 (2.3)
RT
 Yes9 (20.9)
 No27 (62.8)
 NA7 (16.3)
Chemo
 Yes1 (2.3)
 No35 (81.4)
 NA7 (16.3)
Long-term outcome (n = 35)
 PFS (mos)
  MedianNA
  Range3.0–120.0
 OS (mos)
  MedianNA
  Range3.0–120.0
 Recurrence3 (7.9)
  1-yr recurrence-free rate97.0%
  5-yr recurrence-free rate86.2%
  10-yr recurrence-free rate86.2%
 Death1 (2.6)
  1-yr survival rate100.0%
  5-yr survival rate92.9%
  10-yr recurrence-free rate92.9%

ICP = intracranial pressure.

Values represent number of cases (%) unless otherwise indicated. All means are expressed ± SD.

Long-term follow-up data were available in 35 patients and do not include the 1 patient who died shortly after surgery.

All 43 intracranial subependymomas were primary. In 34 cases (79.1%), the tumors were misdiagnosed preoperatively; 14 tumors (32.6%) were misdiagnosed as gliomas, 9 (20.9%) as central neurocytomas, 8 (18.6%) with ependymomas, 1 (2.3%) as medulloblastoma, 1 (2.3%) as meningioma, and 1 (2.3%) as cavernous angioma.

Nine patients received postoperative radiotherapy, and 1 patient received postoperative chemotherapy after tumor recurrence.

Radiological Features of Intracranial Subependymomas

The radiological data are summarized in Table 3. The lesion was located near the Monro foramen in 21 cases, in the fourth ventricle in 7 cases, in the occipital horn of the lateral ventricle in 6 cases, in both the region of the Monro foramen and the 3rd ventricle in 3 cases, in 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 case, in the frontal lobe in 1 case, in the parietal lobe in 1 case, and in the thalamus, midbrain, and temporal lobe in 1 case.

TABLE 3

Radiological characteristics of 43 subependymomas

CharacteristicNo. (%)
Location
 Near the Monro foramen21 (48.8)
 4th ventricle7 (16.3)
 Occipital horn of lateral ventricle6 (14.0)
 Near the Monro foramen & 3rd ventricle3 (7.0)
 Temporal horn of lateral ventricle1 (2.3)
 4th ventricle & pons1 (2.3)
 CPA1 (2.3)
 Frontal lobe1 (2.3)
 Parietal lobe1 (2.3)
 Thalamus, midbrain, & temporal lobe1 (2.3)
Side
 Lt19 (44.2)
 Rt13 (30.2)
 Bilat11 (25.6)
Single or multiple tumor(s)
 Single42 (97.7)
 Multiple1 (2.3)
Shape of tumor
 Spherical39 (90.7)
 Irregular4 (9.3)
Max tumor diameter (cm)
 Mean4.4 ± 1.7
 Range2.0–12.0
CT density
 Hypodensity w/o calcification13 (30.2)
 Hypodensity w/ calcification2 (4.7)
 Isodensity w/o calcification4 (9.3)
 Isodensity w/ calcification1 (2.3)
 Hyperdensity w/o calcification2 (4.7)
 NA21 (48.8)
T1 & T2 signals
 Hypointense T1 & hyperintense T236 (83.7)
 Isointense T1 & hyperintense T22 (4.7)
 NA5 (11.6)
Enhancement
 Spot-like enhancement21 (50.0)
 No enhancement11 (25.6)
 Ring-like enhancement4 (38.5)
 Homogeneous enhancement1
 NA6 (11.6)
Tumor border
 Well defined37 (86.0)
 Poorly defined3 (7.0)
 NA3 (7.0)
Texture
 Microcystic34 (79.1)
 Macrocystic1 (2.3)
 Homogeneous1 (2.3)
 NA7 (16.3)
Preop hydrocephalus
 Yes28 (65.1)
 No15 (34.9)
VP shunt6 (14.0)
 Preop3 (7.0)
 Postop3 (7.0)

The tumor was located on the left side in 19 cases and on the right side in 13 cases; it was bilateral in 11 cases.

Multiple lesions were revealed in only 1 case, while single lesions were observed in 42 cases. Regarding tumor shape, 39 tumors were spherical, and 4 were irregular.

The maximum diameters of the lesions ranged from 2.0 to 12.0 cm (mean 4.4 ± 1.7 cm).

CT images were available in 22 cases. The tumors presented as a hypodensity without calcification in 13 of these cases, a hypodensity with calcification in 2 cases, an isodensity without calcification in 4 cases, an isodensity with calcification in 1 cases, and a hyperdensity without calcification in 2 cases.

MR images were available in 38 cases. The tumors presented as hypointense on T1-weighted images and hyperintense on T2-weighted images in 36 cases and as isointense on T1-weighted images and hyperintense on T2-weighted images in 2 cases. The tumors presented with spot-like enhancement in 21 cases, no enhancement in 11 cases, ring-like enhancement in 4 cases, and homogeneous enhancement in 1 case. According to the radiological findings, the tumor border was well defined in 37 cases and poorly defined in 3 cases. Cystic degeneration was found in 35 subependymomas, including 34 cases with microcystic degeneration and 1 case with macrocystic degeneration.

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). Seventeen tumors were found to originate from the lateral wall of the lateral ventricle, 10 from the septum pellucidum with or without involvement of the lateral wall of the lateral 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 the fourth ventricle. Gross-total resection was achieved in 30 cases, subtotal resection in 10 cases, and partial resection in 3 cases.

TABLE 4

Surgical findings and outcomes in 43 patients with subependymoma*

CharacteristicValue
Intraop blood loss (ml)
 Median200
 Range50–800
Site of tumor origin
 Lateral wall of lateral ventricle17 (39.5)
 Septum pellucidum w/ or w/o lateral wall10 (23.3)
 Brainstem5 (11.6)
 Thalamus w/ or w/o involvement of caudate nucleus or brainstem4 (9.3)
 Cerebellar vermis3 (7.0)
 Frontal, parietal, or occipital lobe3 (7.0)
 Lateral recess of 4th ventricle1 (2.3)
Extent of resection
 Gross total30 (69.7)
 Subtotal10 (23.3)
 Partial3 (7.0)
Surgical duration (hrs)
 Median4.0
 Range1.7–10.0
Periop outcome
 Improved32 (74.4)
 Worsened10 (23.3)
 Death1 (2.3)
Postop complications at discharge
 Limb weakness/paralysis6 (14.0)
 Hydrocephalus requiring VP shunt3 (7.0)
 Cough when drinking/hoarseness/dysphygia2 (4.7)
 Ataxia1 (2.3)
 Aphasia1 (2.3)
 Memory loss1 (2.3)
 Unsmooth speech1 (2.3)

Values represent number of cases unless otherwise indicated.

Postoperative complications present at discharge included limb weakness or paralysis in 6 cases (14.0%), hydrocephalus requiring treatment with a ventriculoperitoneal (VP) shunt in 3 cases (7.0%), cough when drinking and/or hoarseness and/or dysphagia in 2 cases (4.7%), ataxia in 1 case (2.3%), aphasia in 1 case (2.3%), memory loss in 1 case (2.3%), and unsmooth speech in 1 case (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%).

Long-Term Follow-Up

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 progression, and the median PFS was not yet available. The 1-, 5-, and 10-year PFS rates were 97.0%, 86.2%, and 86.2%, respectively. One patient died of recurrence. The median OS was also unavailable. The 1-, 5-, and 10-year survival rates were 100.0%, 92.9%, and 92.9%, respectively. Kaplan-Meier plots of PFS and OS are shown in Fig. 1.

FIG. 1.
FIG. 1.

Kaplan-Meier plots of PFS and OS for 43 patients with intracranial subependymoma. Figure is available in color online only.

Pathological Features of Intracranial Subependymomas

The pathological data are summarized in Table 5. 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).

TABLE 5

Pathological characteristics of 43 subependymomas*

CharacteristicValue (%)
Pure subependymoma34 (79.1)
Subependymoma+ependymoma8 (18.6)
Subependymoma+astrocytoma1 (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)
MBP
 +1 (25.0)
 –3 (75.0)
S100
 +3 (75.0)
 –1 (25.0)
Oligo2
 +3 (75.0)
 –1 (25.0)
NF
 +0 (0.0)
 –3 (100.0)
Nestin
 +2 (100.0)
 –0 (0.0)
1p/19q codeletion
 Yes0 (0.0)
 No5 (100.0)

Not all tumors were evaluated for these parameters. All data available were analyzed.

Immunostaining was positive for GFAP in 15 (88.2%) of 17 cases, for SYN in 3 (30.0%) of 10 cases, for vimentin in 5 (83.3%) of 6 cases, for EMA in 0 (0.0%) of 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 harbored 1p/19q codeletion.

Clinical, Radiological, and Pathological Parameters Associated With PFS and OS

Patient age, sex, the presence of single or multiple tumors, tumor size, tumor border, the presence of hydrocephalus, unilateral or bilateral tumor location, extent of resection, tumor grade, pure or mixed subependymoma, and use of radiotherapy were recorded and analyzed. Parameters significantly associated with longer PFS and OS were identified using log-rank analysis and the Cox regression model (Table 6). Univariate analysis revealed that only poorly defined tumor borders were significantly associated with shorter PFS. The association between shorter PFS and younger patient age was almost significant (p = 0.51), and for that reason it was also included in the multivariate analysis. Multivariate analysis confirmed only poorly defined borders as an independent prognostic factor for PFS (RR 18.655, 95% CI 1.141–304.884, p = 0.040). No factor was revealed to be an independent predictor of OS.

TABLE 6

Results of log-rank analyses of parameters associated with PFS and OS

ParametersPFSOS
χ2p Valueχ2p Value
Age >14 yrs*3.7980.0510.4000.527
Sex0.1100.7400.5560.456
Single or multiple tumors0.1530.6960.0770.782
Tumor size >4.0 cm0.5400.4621.3330.248
Tumor border*8.1200.0040.0770.782
Hydrocephalus1.0970.2951.0000.317
Side2.2320.1351.8000.180
Extent of resection1.3030.2541.3330.248
Tumor grade0.4500.5030.1670.683
Mixed tumor type0.4500.5030.1670.683
RT0.0001.0001.3330.248

Included in multivariate analysis.

Comparison of Cases in Children Versus Patients 14 Years or Older

Stratification of the cases by patient age (< 14 years vs ≥ 14 years) showed many differences (Table 7). Most (96.8%) of the tumors in the patients 14 years or older were located in the supratentorial area, whereas most (66.7%) of those in patients younger than 14 years were located in the infratentorial area (p < 0.001). In the older patient group, most subependymomas (87.1%) were unilateral, whereas most in the younger patient group (58.3%) were bilateral (p = 0.008). Gross-total resection was achieved in 80.6% of patients in the older group and 41.7% of patients in the younger group (p = 0.033). Pathologically, 87.1% of the tumors in patients 14 years of age or older were pure subependymomas, compared with 58.3% in younger patients; the difference was marginally significant (p = 0.097). Moreover, the PFS for older patients was longer than that for those under 14 years (p = 0.051).

TABLE 7

Comparison of features of cases stratified by patient age*

CharacteristicAge Groupp Value
>14 yrs≤14 yrs
No. of cases3112
Sex
 M14 (45.2)8 (66.7)0.206
 F17 (54.8)4 (33.3)
Tumor location
 Supratentorial30 (96.8)4 (33.3)<0.001
 Subtentorial1 (3.2)8 (66.7)
Sides affected
 Unilat27 (87.1)5 (41.7)0.008
 Bilat4 (12.9)7 (58.3)
Preop hydrocephalus
 Yes22 (71.0)6 (50.0)0.349
 No9 (29.0)6 (50.0)
Postop hydrocephalus
 Yes3 (9.7)0 (0.0)0.548
 No28 (90.3)12 (100.0)
Extent of resection
 Gross total25 (80.6)5 (41.7)0.033
 Subtotal or partial6 (19.4)7 (58.3)
Pathology
 Pure subependymoma27 (87.1)7 (58.3)0.097
 Mixed subependymoma4 (12.9)5 (41.7)
Long-term outcome
 PFS (mos)0.051
 OS (mos)0.527

Values represent numbers of cases (%) unless otherwise indicated.

Illustrative Cases

Case 21

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 intermittent headache for 1 year. Neurological examination revealed no positive signs. The lesion showed a hypodensity adjacent to the Monro foramen on CT (Fig. 2A and B) and long T1 and long T2 signals with microcystic degeneration and without enhancement on MR images (Fig. 2CH). The patient underwent a left frontal transcallosal approach, and gross-total resection of the tumor was achieved (Fig. 2IK). During the operation, the tumor was found to be a gray-white mass in the left lateral and third ventricles. Postoperative pathological examination confirmed the diagnosis of subependymoma (Fig. 2O). The patient was discharged 9 days after surgery without any neurological deterioration. She was followed up for 3 years, and no recurrence was found (Fig. 2LN).

FIG. 2.
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.

Case 36

A 3-year-old child was admitted to our hospital with a radiological diagnosis of a mass occupying the fourth ventricle and secondary hydrocephalus. He was reported to have been suffering from nausea for 1.5 months and sleepiness for 1 month. Neurological examination revealed papillary edema. CT revealed a hyperdensity in the fourth ventricle (Fig. 3). MR images revealed a lesion with long T1 and long T2 signals as well as spot-like enhancement (Fig. 3BG). A VP shunt was placed, and 7 days later, surgery was performed via a posterior median approach with the intention of total tumor removal (Fig. 3HJ). During the operation, the tumor was found to be a gray-red soft mass with well-defined borders. Postoperative pathology revealed the diagnosis of a subependymoma with increased cellularity (WHO Grade I and II) (Fig. 3K). The patient was discharged 8 days after surgery without any other treatment. Seven months later, the patient was readmitted to our hospital with recurrent headache. Radiological examination revealed a recurrent mass in the fourth ventricle (Fig. 4AF). A second operation was performed, and grosstotal resection of the recurrent tumor was achieved (Fig. 4GK). Pathological examination resulted in the diagnosis of anaplastic ependymoma (Fig. 4L). After the operation, the patient underwent radiotherapy and chemotherapy. At the last follow-up 21 months after the primary surgery, the patient was still alive.

FIG. 3.
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.

FIG. 4.
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.

Discussion

Intracranial subependymoma is a rare central nervous system tumor that is often misdiagnosed as other diseases. To date, few series of intracranial subependymoma have been reported due to its extremely low incidence. Approximately 60,000 patients with intracranial tumors were surgically treated in our hospital from 2003 to 2013. Among them, 43 patients were found to have pathologically confirmed intracranial subependymoma. To the best of our knowledge, this is the second largest series of intracranial subependymoma from a single neurosurgical center.

Lower Incidence of Intracranial Subependymoma and Its Relationship With Ependymomas

The frequency of subependymoma in our hospital was lower than previously reported. A 0.7% incidence of subependymoma was previously reported among 1000 patients with pathologically proven intracranial neoplasms, and an incidence of 0.4% among 1000 asymptomatic patients has been reported based on autopsy findings.13 In our center, the estimated incidence of intracranial subependymoma was 0.07%.

Subependymoma appears most likely to arise from subependymal glial precursor cells.3,16,17 Ependymal glial precursor cells are bipotential cells, with the ability to differentiate into either an ependymal cell or an astrocyte. Among 43 subependymoma cases, we found 8 cases with mixed ependymoma, and 1 with mixed astrocytoma. Our finding supports the bipotential hypothesis of ependymal glial precursor cells.

Most subependymomas are benign with a low recurrence rate. However, a few progress as anaplastic ependymoma. Recurrence was seen in 3 of our 43 patients, including 1 with recurrent subependymoma, 1 with anaplastic ependymoma, and 1 with an unavailable pathological diagnosis.

Clinical-Radiological Differential Diagnoses for Intracranial Subependymomas

According to the location in the ventricular system and the unique radiological features of intracranial subependymomas, it is not difficult to distinguish them from other tumors. According to our analysis, 39 (90.7%) of 43 cases were located in the ventricular system. Radiologically, most present with hypodensity without calcification on CT and long T1 and T2 signals with no or mild enhancement on MR images. The most characteristic MR feature of intracranial subependymoma is microcysts within the tumors.

Intracranial subependymomas should be differentiated from other intracranial tumors, including ependymomas, medulloblastomas, astrocytomas, central neurocytomas, and meningiomas.

For subependymomas in the area of the Monro foramen, central neurocytoma, glioma, and ependymoma should be included in the differential diagnosis. Neurocytomas present with isodensity or hyperdensity with mild to moderate enhancement on CT scan.15 Spicules identified at the tumor periphery interfacing with the lateral ventricle walls result in a scalloping appearance, contributing greatly to the specificity and accuracy of the diagnosis.14 Subependymal giant cell astrocytomas (SGCAs) are a common manifestation of tuberous sclerosis. SGCAs present as areas of hypodensity with calcification on CT. After injection of a contrast agent, they show mild to moderate enhancement.15 Most ependymomas have a cystic component, and MR contrast enhancement has been reported to show an enhancing nodule within the wall of a cyst, heterogeneous enhancement of cystic and solid lesions, and homogeneous enhancement of solid lesions.5

For subependymomas in the fourth ventricle, medulloblastoma and low-grade astrocytoma should be included in the differential diagnosis. In adults, most medulloblastomas present as areas of hyperdensity with mild to moderate enhancement on CT and show a low-density area consistent with cystic and necrotic degeneration. In children, the mass has been reported to present as an area of hyperdensity with markedly homogeneous enhancement and to show no cystic or necrotic degeneration.2 Most low-grade astrocytomas present with long T1 and long T2 signals on MR images and no or mild enhancement, similar to subependymomas. The microcystic signal within the tumor is typically indicative of subependymoma instead of astrocytoma.

Subependymomas within the parenchyma are very difficult to differentiate from gliomas. In 3 of our cases, parenchymal subependymoma were initially misdiagnosed as gliomas because there were not enough features for differentiation.

Hydrocephalus

Twenty-eight patients experienced hydrocephalus preoperatively, and 3 (10.7%) of them were treated with VP shunting before tumor removal and 1 (3.6%) was treated with VP shunting after tumor removal. All 3 patients who were treated with VP shunts preoperatively were children with a tumor in the fourth ventricle. The patient who had a VP shunt placed postoperatively was an adult with a tumor located near the Monro foramen and in the third ventricle. Preoperative hydrocephalus was resolved by tumor removal in 24 (85.6%) of 28 cases.

Fifteen patients did not present with hydrocephalus preoperatively; 2 of these patients experienced acute hydrocephalus after tumor removal and required VP shunt placement. Both patients were adults with a tumor located near the Monro foramen or in the occipital horn. The frequency of acute postoperative hydrocephalus was 13.3% (2 of 15 cases).

Of the 9 patients with a tumor in the posterior fossa, 7 were complicated by hydrocephalus. In these cases, preoperative VP shunting was recommended to avoid acute cerebellar tonsillar hernia. For the 34 patients with a supratentorial tumor in our series, however, ventriculo-peritoneal shunting was not performed until acute postoperative hydrocephalus occurred.

Radiotherapy, Recurrence, and Survival

Twelve patients were treated with postoperative radio-therapy. Although radiotherapy did not show a significant association with longer survival, it was recommended for patients who had subtotal or partial resection of their tumors and for those with mixed tumor types.

Kaplan-Meier plots of PFS and OS are shown in Fig. 1. Subependymoma is a benign tumor, and long-term survival can be expected of these patients.

Comparison of Cases in Children Versus Patients 14 Years or Older

There were many differences with respect to tumor location, sides, removal degree, pathology, and survival when the patient group was divided based on age (Table 7). In patients 14 years old or older, these tumors tended to be pure subependymomas located in the unilateral supratentorial area and total removal tends to be easy and PFS tends to be longer. By contrast, in younger patients subependymomas tended to be mixed tumors involving the bilateral infratentorial area, with a lower total removal rate and shorter PFS. All of the above differences suggest that the tumor origins, biological behavior, and prognoses of subependymomas might differ between adults and children.

Clinical, Radiological, and Pathological Parameters Associated With Prognosis

To examine associations with PFS and OS in patients with surgically treated subependymoma, we analyzed clinical, radiological and pathological parameters using the log-rank test and Cox regression model (Table 6). Poorly defined borders were significantly associated with worse prognosis, and the association between younger age and shorter PFS almost reached significance. Multivariate analysis revealed 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). No factor was revealed to be an independent predictor of OS.

Study Limitations

This was a retrospective review of surgically treated cases of a rare intracranial tumor. This series of cases included a small patient group without any control group. Typical biases exist, and the statistical analysis is limited, given the small number of cases and the retrospective nature of the series. There is concern that correlation may be an artifact of the small group size and lack of controls. Therefore, other series of intracranial subependymomas were analyzed in the discussion, fortifying our observation with similar results.

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 prognostic factor for shorter PFS. The different features between features in cases involving patients older or younger than 14 years suggest that they might have different tumor origins, biological behaviors, and prognoses.

Author Contributions

Conception and design: Jia, Bi, Ren. Acquisition of data: Jia, Bi, Ren. Analysis and interpretation of data: Jia, Bi, Ren. Drafting the article: Bi, Ren. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Jia. Statistical analysis: Bi, Ren. Administrative/technical/material support: Jia, Zhang. Study supervision: Jia, Zhang.

References

  • 1

    Artico MBardella LCiappetta PRaco A: Surgical treatment of subependymomas of the central nervous system. Report of 8 cases and review of the literature. Acta Neurochir (Wien) 98:25311989

  • 2

    Bourgouin PMTampieri DGrahovac SZLéger CDel Carpio RMelançon D: CT and MR imaging findings in adults with cerebellar medulloblastoma: comparison with findings in children. AJR Am J Roentgenol 159:6096121992

  • 3

    Fu YSChen ATKay SYoung H: Is subependymoma (subependymal glomerate astrocytoma) an astrocytoma or ependymoma? A comparative ultrastructural and tissue culture study. Cancer 34:199220081974

  • 4

    Fujisawa HHasegawa MUeno M: Clinical features and management of five patients with supratentorial subependymoma. J Clin Neurosci 17:2012042010

  • 5

    Furie DMProvenzale JM: Supratentorial ependymomas and subependymomas: CT and MR appearance. J Comput Assist Tomogr 19:5185261995

  • 6

    Hou ZWu ZZhang JZhang LTian RLiu B: Clinical features and management of intracranial subependymomas in children. J Clin Neurosci 20:84882013

  • 7

    Hou ZWu ZZhang JZhang LTian RLiu B: Lateral ventricular subependymomas: an analysis of the clinical features of 27 adult cases at a single institute. Neurol India 60:3793842012

  • 8

    Im SHPaek SHChoi YLChi JGKim DGJung HW: Clinicopathological study of seven cases of symptomatic supratentorial subependymoma. J Neurooncol 61:57672003

  • 9

    Jain AAmin AGJain PBurger PJallo GILim M: Subependymoma: clinical features and surgical outcomes. Neurol Res 34:6776842012

  • 10

    Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

  • 11

    Maiuri FGangemi MIaconetta GSignorelli FDel Basso De Caro M: Symptomatic subependymomas of the lateral ventricles. Report of eight cases. Clin Neurol Neurosurg 99:17221997

  • 12

    Matsumura AAhyai AHori A: Symptomatic subependymoma with nuclear polymorphism. Neurosurg Rev 10:2912931987

  • 13

    Matsumura AAhyai AHori ASchaake T: Intracerebral subependymomas. Clinical and neuropathological analyses with special reference to the possible existence of a less benign variant. Acta Neurochir (Wien) 96:15251989

  • 14

    Niiro TTokimura HHanaya RHirano HFukukura YSugiyma K: MRI findings in patients with central neurocytomas with special reference to differential diagnosis from other ventricular tumours near the foramen of Monro. J Clin Neurosci 19:6816862012

  • 15

    Nishio SMorioka TSuzuki SFukui M: Tumours around the foramen of Monro: clinical and neuroimaging features and their differential diagnosis. J Clin Neurosci 9:1371412002

  • 16

    Ragel BTOsborn AGWhang KTownsend JJJensen RLCouldwell WT: Subependymomas: an analysis of clinical and imaging features. Neurosurgery 58:8818902006

  • 17

    Rushing EJCooper PBQuezado MBegnami MCrespo ASmirniotopoulos JG: Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol 85:2973052007

  • 18

    Sceinker IM: Subependymoma: a newly recognized tumor of subependymal derivation. J Neurosurg 2:2322401945

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Article Information

Correspondence Wang Jia, Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili No. 6, Beijing 100050, China. email: jwttyy@sina.com.cn.

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.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Kaplan-Meier plots of PFS and OS for 43 patients with intracranial subependymoma. Figure is available in color online only.

  • View in gallery

    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.

  • View in gallery

    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.

  • View in gallery

    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.

References

  • 1

    Artico MBardella LCiappetta PRaco A: Surgical treatment of subependymomas of the central nervous system. Report of 8 cases and review of the literature. Acta Neurochir (Wien) 98:25311989

  • 2

    Bourgouin PMTampieri DGrahovac SZLéger CDel Carpio RMelançon D: CT and MR imaging findings in adults with cerebellar medulloblastoma: comparison with findings in children. AJR Am J Roentgenol 159:6096121992

  • 3

    Fu YSChen ATKay SYoung H: Is subependymoma (subependymal glomerate astrocytoma) an astrocytoma or ependymoma? A comparative ultrastructural and tissue culture study. Cancer 34:199220081974

  • 4

    Fujisawa HHasegawa MUeno M: Clinical features and management of five patients with supratentorial subependymoma. J Clin Neurosci 17:2012042010

  • 5

    Furie DMProvenzale JM: Supratentorial ependymomas and subependymomas: CT and MR appearance. J Comput Assist Tomogr 19:5185261995

  • 6

    Hou ZWu ZZhang JZhang LTian RLiu B: Clinical features and management of intracranial subependymomas in children. J Clin Neurosci 20:84882013

  • 7

    Hou ZWu ZZhang JZhang LTian RLiu B: Lateral ventricular subependymomas: an analysis of the clinical features of 27 adult cases at a single institute. Neurol India 60:3793842012

  • 8

    Im SHPaek SHChoi YLChi JGKim DGJung HW: Clinicopathological study of seven cases of symptomatic supratentorial subependymoma. J Neurooncol 61:57672003

  • 9

    Jain AAmin AGJain PBurger PJallo GILim M: Subependymoma: clinical features and surgical outcomes. Neurol Res 34:6776842012

  • 10

    Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

  • 11

    Maiuri FGangemi MIaconetta GSignorelli FDel Basso De Caro M: Symptomatic subependymomas of the lateral ventricles. Report of eight cases. Clin Neurol Neurosurg 99:17221997

  • 12

    Matsumura AAhyai AHori A: Symptomatic subependymoma with nuclear polymorphism. Neurosurg Rev 10:2912931987

  • 13

    Matsumura AAhyai AHori ASchaake T: Intracerebral subependymomas. Clinical and neuropathological analyses with special reference to the possible existence of a less benign variant. Acta Neurochir (Wien) 96:15251989

  • 14

    Niiro TTokimura HHanaya RHirano HFukukura YSugiyma K: MRI findings in patients with central neurocytomas with special reference to differential diagnosis from other ventricular tumours near the foramen of Monro. J Clin Neurosci 19:6816862012

  • 15

    Nishio SMorioka TSuzuki SFukui M: Tumours around the foramen of Monro: clinical and neuroimaging features and their differential diagnosis. J Clin Neurosci 9:1371412002

  • 16

    Ragel BTOsborn AGWhang KTownsend JJJensen RLCouldwell WT: Subependymomas: an analysis of clinical and imaging features. Neurosurgery 58:8818902006

  • 17

    Rushing EJCooper PBQuezado MBegnami MCrespo ASmirniotopoulos JG: Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol 85:2973052007

  • 18

    Sceinker IM: Subependymoma: a newly recognized tumor of subependymal derivation. J Neurosurg 2:2322401945

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