J Orthop Sci DOI 10.1007/s00776-014-0585-4
CASE REPORT
Intramedullary cervicothoracic subependymoma: report of three cases and review of the literature Zhiwei Wu • Akio Iwanami • Akimasa Yasuda • Shuji Mikami • Yoshiaki Toyama • Masaya Nakamura
Received: 25 November 2013 / Accepted: 1 May 2014 Ó The Japanese Orthopaedic Association 2014
Introduction A subependymoma is a tumor of the central nervous system. It is usually found in an intraventricular location. Most intraventricular subependymomas are subclinical in nature, whereas those located on the spine are inevitably accompanied by myelopathy. Spinal cord subependymomas are extremely rare, however. Here we report three cases of intramedullary subependymoma in the cervicothoracic region, and compare their features and surgical follow-up to previously published cases of this tumor type.
Report of cases Case 1 A 19-year-old male presented with bilateral knee pain that had existed for the past 6 years. He complained of bilateral lower limb weakness, and was not able to walk prior
Z. Wu A. Iwanami A. Yasuda Y. Toyama M. Nakamura (&) Department of Orthopaedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjukuku, Tokyo 160-8582, Japan e-mail: [email protected] Z. Wu Department of Orthopaedic Surgery, The First Affiliated Hospital, Xiamen University, No.55 Zhenhai Road, Siming District, Xiamen 361003, China S. Mikami Department of Pathology, Keio University School of Medicine, Shinanomachi 35, Shinjukuku, Tokyo 160-8582, Japan
to admission. Neurological examination revealed muscle weakness in the left leg, but no sensory disturbance. There were no symptoms of bladder dysfunction or stool incontinence. The Japanese Orthopaedic Association score (JOA score) was 9/11. Preoperative magnetic resonance imaging (MRI) demonstrated a left eccentric intramedullary lesion from C6 to T10, which had a clear margin and was hyperintense on T2-weighted images (Fig. 1a, b) without gadolinium (Gd) enhancement. Ganglioglioma, astrocytoma, and ependymoma were considered in the differential diagnosis. The patient underwent a C6 laminoplasty, C7–T10 laminectomy, and posterior midline myelotomy, and a firm and dark yellowish tumor was revealed. The intraoperative histological diagnosis was low-grade glioma. The mass was enucleated piece by piece from the well-demarcated left eccentric area. A cavitron ultrasonic surgical aspirator (CUSA) was used to debulk the intramedullary tumor. No obvious alterations of the sensory evoked potential (SEP) or the motor evoked potential (MEP) were recorded during the operation. Immunohistochemistry revealed that the tumor cells were positive for glial fibrillary acidic protein (Fig. 1c), S100P, and CD99; dot-like positive for epithelial membrane antigen; partially positive for nestin; and negative for Olig2, NFP-MH, NeuN, and CD34. The MIB1 labeling index was 2.1 % (Fig. 1d). Taken together, these results led to a final diagnosis of subependymoma (WHO grade I). After the resection, the residual tumor was treated with adjuvant radiotherapy. The patient developed severe back pain, muscle weakness in his left leg (MMT grade 3–4), and sensory disturbance (hyperthesia in the trunk region and hypothesia below the knee) around 7 days after surgery. At the time of discharge, the JOA score was 7.5/11. MRI after 41 months revealed no change in the size of the residual tumor.
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Fig. 1 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C6–T7 level. WI weighted images, MRI magnetic resonance imaging. b Axial T2WI MRI showing a multilocular tumor located on the left side of the spinal cord. c Representative section
stained with anti-GFAP antibody. Tumor cells are diffusely positive for GFAP (409). GFAP glial fibrillary acidic protein. d Representative section stained for MIB1 showing a low proliferation index (409)
Case 2
tumor to be firm and dark yellowish. The intraoperative histological diagnosis was low-grade glioma. When the left portion of the tumor was subjected to gross subtotal resection, MEP of the left lower extremity suddenly disappeared, and never recovered after that (Fig. 2c). Therefore, gross total resection was halted; the ventral and right portions of the tumor could not be resected. CUSA was also used for debulking of the intramedullary tumor. The final diagnosis was subependymoma. The patient developed left lower extremity numbness and complained of left shoulder pain during the postoperative period. At the time of discharge, the power grade of the left leg below the hip was 1–3, and the JOA score was 6.5/11. The patient has been followed up for 29 months. No adjuvant radiotherapy was administered. MRI after 28 months revealed no change in the size of the residual tumor.
A 60-year-old female presented with bilateral lower extremity numbness and a walking disability that had existed for 12 months. She complained of right leg pain. Neurological examination revealed motor weakness in the bilateral ankles (MMT grade 4–5). Sensory impairment existed in the dermatome below the L4 level. There were no symptoms of bladder dysfunction or stool incontinence. The JOA score was 9/11 before the operation. MRI demonstrated multiple lesions in the ventral spinal cord from C5 to T2 that had clear margins and were hyperintense on T2-WI (Fig. 2a, b) without Gd enhancement. Toxocariasis canis and subarachnoid cyst were considered in the differential diagnosis. The patient underwent a C6–T1 laminoplasty and a T2 laminectomy. Posterior midline myelotomy showed the
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Spinal intramedullary subependymoma
Fig. 2 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C5–T2 level. b Axial T2WI MRI showing a multilocular tumor invading the spinal cord from three directions. c Changes in
MEP waveforms during surgery in case 2. R right, L left, TA tibialis anterior, GS gastrocnemius. The amplitude of the control waveform is defined as 100 %
Case 3
There was also an intramedullary syrinx. The patient underwent a C6–T1 laminoplasty and a T2–4 laminectomy, and the tumor revealed by posterior midline myelotomy was firm and white-reddish. The intraoperative histological diagnosis was low-grade glioma. After 50 % of the tumor had been resected, the MEP waveform on the right lower extremity decreased and the procedure was suspended until the waveform recovered. During the final resection of the tumor in the ventral side, the MEP disappeared and never recovered (Fig. 3c). The final diagnosis was subependymoma. After surgery, the patient’s bladder dysfunction improved, but he complained of left shoulder pain postoperatively. At the time of discharge, his right lower
A 49-year-old male presented with back pain of duration 1.5 years. He complained of right lower extremity numbness and a walking disability that had existed for 6 months. Neurological examination revealed motor weakness below the right hip (power of 4/5). Sensory impairment existed in the dermatome below C5. He had frequent bladder dysfunction but no stool incontinence. The JOA score was 6/11 before the operation. MRI revealed a right eccentric lesion in the spinal cord from C6 to T3. The lesion had a clear margin, and was hyperintense on T2-WI (Fig. 3a, b), with partial enhancement after paramagnetic contrast.
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Fig. 3 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C6–T3 level. b Axial T2WI MRI showing a tumor located on the right side of the spinal cord. c Changes in MEP
waveforms during surgery in case 3. R right, L left, TA tibialis anterior, GS gastrocnemius. The amplitude of the control waveform is defined as 100 %
extremity numbness had shown no improvement, the right lower extremity power grade was 2–3, and the JOA score was 5/11. The patient has been followed up for 30 months. No adjuvant radiotherapy was administered. Postoperative MRI revealed residual tumor at the C7–T1 level, and MRI after 28 months revealed no change in the size of the residual tumor.
of intracranial tumors, the incidence of cerebral subependymoma is very low (0.2–0.7 %). The occurrence of spinal subependymoma is also exceedingly rare. To our knowledge, only 69 cases have been described in the literature since the first case was reported by Boykin et al. in [1]. There have been 19 cases [1–13] of tumors in the cervicothoracic region, only 15 of which [2–4, 6, 8–13] were intramedullary in nature. The patients in those cases underwent surgery (not just biopsy). Table 1 summarizes the current three cases along with the ten cases that were documented in detail previously [2, 3, 6, 8, 9, 12, 13]. Since a subependymoma is classified as a benign tumor (WHO grade I), and it usually has a distinct cleavage plane,
Discussion A subependymoma is a rare kind of tumor that can occur throughout the central nervous system. Within the category
123
M
F
F
50
53
28
37
20
33
24
45
Vaquero et al. [6]
Pagni et al. [8]
Salvati et al. [9]
Krishnan et al. [12]
Wu et al. [13]
M
F
M
19
60
49
F
M
M
F
M
C6–T3
C5–T2
C6–T10
C5–T1
C4–T3
C7–T6
C7–T5
C3–T7
C4–T7
C5–T1
C3–T1
C6–T2
C3–T1
Location
STR
PR
STR
GTR
GTR
GTR
GTR
STR
TR
TR
TR
GTR
PR
GTR
a
Surgery
Right lower extremity MEP decreased
Left lower extremity MEP decreased
No change
No description
No description
No description
No description
No description
No description
No description
JOA score 6/11
JOA score 9/11
JOA score 9/11
McCormick grade Ib
McCormick grade II
McCormick grade Ib
McCormick grade II
Grade 3/5 power in right upper limb
Progressive tetraparesis, hypesthesia and sphincter disturbances
Amyotrophy of both hands and gait disturbances
Progressive weakness affecting right limbs
Normal
No description No description
Mild left hemiparesis
Preoperative status
A progressive diminution of amplitude followed by partial recovery on the left
Intraoperative SEP/MEP
JOA score 5/11
JOA score 6.5/11
JOA score 7.5/11
McCormick grade II
McCormick grade III
McCormick grade II
McCormick grade III
No progression of symptoms
Slight improvement
Motility improved in hands but decreased in leg; ataxic gait and inexhaustible clonus
Marked paraparesis
Spasticity and left leg weakness
Marked worsening of posterior column function in left hand and leg
Postoperative status
a
2 years later
TR total resection, GTR gross total resection, STR subtotal resection, PR partial resection, SEP sensory evoked potential, MEP motor evoked potential, JOA Japanese Orthopaedic Association
Present
F
48
Lee et al. [3]
F
44
Salcman et al. [2]
Sex
Age
Authors
Table 1 Intramedullary cervicothoracic subependymoma cases
Spinal intramedullary subependymoma
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Z. Wu et al. Table 2 MRI findings of cervicothoracic intramedullary subependymomas Author
Age
Sex
MRI Location
T1WI
Lee et al. [3]
48
M
Vaquero et al. [6]
50
F
Intramedullary tumor
Pagni et al. [8]
53
M
Enlargement of the intramedullary mass
T2WI
?GA
Syrinx
ND
Enlargement and increased signal intensity
Salvati et al. [9]
28
M
Intramedullary tumor
Krishnan et al. [12]
37
F
ND
ND
Hyperintense
Mild heterogeneous
Wu et al. [13]
20
F
ND
Mild hypo
Mild hyper
Patchy
ND
33 24
M F
ND ND
Iso Iso
Hyper Mild hyper
No Mildly patchy
ND ND
45
F
ND
Mild hypo
Hyper
No
ND
19
M
Left eccentric
Iso
Hyper
No
(-)
60
F
Ventral multiple
Iso
Hyper
No
(-)
49
M
Right eccentric
Iso
Hyper
Patchy
(?)
Present
ND no description, MRI magnetic resonance imaging, iso isointense
we may anticipate a good clinical outcome after an operation performed with the aid of an operating microscope. While this may be true in other areas of the spinal cord or brain ventricles, it is apparently not the case in the cervicothoracic region. As Table 1 reveals, the conditions of most of the patients with intramedullary subependymoma worsened in the postoperative period, although several patients showed some improvement after a long period of rehabilitation [2, 6, 13]. These less-than-optimal outcomes may be related to the surgeon’s operational skills, or to the vulnerability of the spinal cord in the cervicothoracic region [14]. In all of our cases, tumor resection was performed under MEP/SEP monitoring in accordance with an alarm point (more than 30 % of the control amplitude would be safe) for intraoperative spinal cord monitoring, as proposed by the Japanese Society for Spine Surgery and Related Research [15]. However, applying this procedure did not enable the development of new deficits to be avoided, let alone the achievement of gross total resection. Intriguingly, one of these patients presented new deficits after surgery without any drastic change in the MEP waveform during operation. Therefore, these poor outcomes may also be due to other factors, such as postlaminectomy kyphosis and intramedullary microcirculation. Indeed, the spinal cord vasculature around the cervicothoracic region is not abundant as that around the cervical or lumbar region [14, 16]. Additional case studies may lead to an explanation. For surgical treatment, Jang et al. [17] reported that aggressive surgery for this tumor may cause either worsening of an existing deficit or the development of new deficits. Our outcomes are completely in line with their report. Subtotal resection or even partial resection with duraplasty should be considered for the treatment of subependymoma, especially in the
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cervicothoracic region. There are also some reports supporting the effectiveness of postoperative radiotherapy [17, 18], although this remains controversial. More experience and a longer follow-up would be required to establish its effectiveness. Subependymomas studied by MRI typically show spinal cord enlargement, are hypointense to isointense on T1WI, hyperintense on T2WI, and occasionally display faint enhancement after Gd injection [10, 11, 13, 17–27]. The MRI findings of all reported intramedullary cervicothoracic subependymomas are shown in Table 2. Our results are consistent with those described in the literature. The eccentric location, the segmental fusiform dilatation of the cord, the high rate of nonenhancement, and the syringomyelia occasionally associated with subependymomas are features that distinguish them from ependymomas, which usually form in the center of the cord and present as a wellenhanced lesion accompanied by a cyst [10, 17, 20, 21, 26, 28]. The intramedullary ependymoma is believed to originate in the wall of the central canal, and is classified as WHO grade II. In contrast, subependymomas may develop into huge masses and compress the cord severely, causing their characteristic eccentric localization, which is not distinguishable on MRI [13]. It is difficult to differentiate a subependymoma from other intramedullary tumors using only MRI. In the three cases reported here, the tumors were located at multiple levels and multilocular in shape, which might be considered characteristics of this tumor type on MRI. The pathogenesis of subependymoma is still controversial. When Scheinker [29] first described this type of tumor in 1945, he proposed that it arises from the subependymal cell plate or the residual periventricular matrix layer. Later, Boykin et al. [1] proposed that it originates from
Spinal intramedullary subependymoma
subependymal astrocytes, and consequently named these tumors subependymal glomerate astrocytomas. Fu et al. [30] used electron microscopy to study a tumor consisting of both ependymoma and subependymoma. They found a similarity of cellular components at the ultrastructural level and concluded that a subependymoma is a variety of ependymoma. In 1984, Moss [31] found cells similar to ependymal glial precursor cells in the adult subependymal cell layer, and concluded that subependymomas were separate entities from ependymomas and astrocytomas. Nagashima et al. [5] proposed that the macroscopic eccentric location of subependymomas suggests that they are derived from the subependymal cell plate. Since the immunohistochemical profile tended to support a glial origin, subependymomas were grouped with low-grade glial tumors [32]. Another theory is that they originate from tanycytes [33]. Tanycytes are normally located in the subependymal zone, and have long processes spanning the pial to the ventricular surface. Ultrastructurally, they show features of both astrocytic and ependymal cells. Occasionally, subependymomas are associated with heterotopic leptomeningeal glial tissue, and they have even been found in identical twins. However, Krishnan et al. [12] noted that a better explanation for their eccentric and subpial locations is that spinal subependymomas may be descended from subpial spinal white matter progenitor cells. In conclusion, the surgical outcomes of treating intramedullary cervicothoracic subependymomas were not satisfactory in these three cases, although the tumors were biologically benign. More reports describing these problematic tumors will help us to better understand their etiology and improve their treatment. Conflict of interest of interest.
The authors declare that they have no conflict
Consent section The patients and/or their families were informed that the data, radiographs, and photographs from their cases would be submitted for publication, and gave their consent.
References 1. Boykin FC, Cowen D, Iannucci CA, Wolf A. Subependymal glomerate astrocytomas. J Neuropathol Exp Neurol. 1954;13:30–49. 2. Salcman M, Mayer R. Intramedullary subependymoma of the cervical spinal cord: case report. Neurosurgery. 1984;14:608–11. 3. Lee KS, Angelo JN, McWhorter JM, Davis CH Jr. Symptomatic subependymoma of the cervical spinal cord. Report of two cases. J Neurosurg. 1987;67:128–31. 4. Herrmann HD, Neuss M, Winkler D. Intramedullary spinal cord tumors resected with CO2 laser microsurgical technique: recent experience in fifteen patients. Neurosurgery. 1988;22:518–22. 5. Nagashima M, Isu T, Iwasaki Y, Miyamachi K, Akino M, Abe H, Tashiro K, Miyasaka K. Intramedullary subependymoma of the cervical spinal cord. Case report. Neurol Med Chir (Tokyo). 1988;28:303–8 (in Japanese).
6. Vaquero J, Martinez R, Vegazo I, Ponton P. Subependymoma of the cervical spinal cord. Neurosurgery. 1989;24:625–7. 7. Lach B, Russell N, Benoit B. Atypical subependymoma of the spinal cord: ultrastructural and immunohistochemical studies. Neurosurgery. 1990;27:319–25. 8. Pagni CA, Canavero S, Giordana MT, Mascalchi M, Arnetoli G. Spinal intramedullary subependymomas: case report and review of the literature. Neurosurgery. 1992;30:115–7. 9. Salvati M, Raco A, Artico M, Artizzu S, Ciappetta P. Subependymoma of the spinal cord. Case report and review of the literature. Neurosurg Rev. 1992;15:65–9. 10. Jallo GI, Zagzag D, Epstein F. Intramedullary subependymoma of the spinal cord. Neurosurgery. 1996;38:251–7. 11. White JB, Miller GM, Layton KF, Krauss WE. Nonenhancing tumors of the spinal cord. J Neurosurg Spine. 2007;7:403–7. 12. Krishnan SS, Panigrahi M, Pendyala S, Rao SI, Varma DR. Cervical subependymoma: a rare case report with possible histogenesis. J Neurosci Rural Pract. 2012;3:366–9. 13. Wu L, Yang T, Deng X, Yang C, Zhao L, Fang J, Wang G, Yang J, Xu Y. Surgical outcomes in spinal cord subependymomas: an institutional experience. J Neurooncol. 2014;116:99–106. 14. Li XF, Dai LY. Acute central cord syndrome: injury mechanisms and stress features. Spine. 2010;35:E955–64. 15. Kobayashi S, Matsuyama Y, Shinomiya K, Kawabata S, Ando S, Kanchiku T, Saito T, Takahashi M, Ito Z, Muramoto A, Fujiwara Y, Kida K, Yamada K, Wada K, Yamamoto N, Satomi K, Tani T. Alarm point of transcranial electrical stimulation motor evoked potentials for intraoperative spinal cord monitoring: a prospective multicenter study of Japanese Society for Spine Surgery and Related Research (JSSR). Rinshou Seikeigeka (Clinical Orthopaedic Surgery). 2012;47:823–7. 16. Martirosyan NL, Feuerstein JS, Theodore N, Cavalcanti DD, Spetzler RF, Preul MC. Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions. J Neurosurg Spine. 2011;15:238–51. 17. Jang WY, Lee JK, Lee JH, Kim JH, Kim SH, Lee KH, Lee MC. Intramedullary subependymoma of the thoracic spinal cord. J Clin Neurosci. 2009;16:851–3. 18. Nowak A, Marchel A. Surgical treatment of intraventricular ependymomas and subependymomas. Neurol Neurochir Pol. 2012;46:333–43. 19. Hoeffel C, Boukobza M, Polivka M, Lot G, Guichard JP, Lafitte F, Reizine D, Merland JJ. MR manifestations of subependymomas. AJNR Am J Neuroradiol. 1995;16:2121–9. 20. Dario A, Fachinetti P, Cerati M, Dorizzi A. Subependymoma of the spinal cord: case report and review of the literature. J Clin Neurosci. 2001;8:48–50. 21. Sarkar C, Mukhopadhyay S, Ralte AM, Sharma MC, Gupta A, Gaikwad S, Mehta VS. Intramedullary subependymoma of the spinal cord: a case report and review of literature. Clin Neurol Neurosurg. 2003;106:63–8. 22. Shimada S, Ishizawa K, Horiguchi H, Shimada T, Hirose T. Subependymoma of the spinal cord and review of the literature. Pathol Int. 2003;53:169–73. 23. Ragel BT, Osborn AG, Whang K, Townsend JJ, Jensen RL, Couldwell WT. Subependymomas: an analysis of clinical and imaging features. Neurosurgery. 2006;58:881–90. 24. Rushing EJ, Cooper PB, Quezado M, Begnami M, Crespo A, Smirniotopoulos JG, Ecklund J, Olsen C, Santi M. Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol. 2007;85:297–305. 25. Orakcioglu B, Schramm P, Kohlhof P, Aschoff A, Unterberg A, Halatsch ME. Characteristics of thoracolumbar intramedullary subependymomas. J Neurosurg Spine. 2009;10:54–9. 26. Jabri HE, Dababo MA, Alkhani AM. Subependymoma of the spine. Neurosciences (Riyadh). 2010;15:126–8.
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Z. Wu et al. 27. Iwasaki M, Hida K, Aoyama T, Houkin K. Thoracolumbar intramedullary subependymoma with multiple cystic formation: a case report and review. Eur Spine J. 2013;22(Suppl 3):S317–20. 28. Kremer P, Zoubaa S, Schramm P. Intramedullary subependymoma of the lower spinal cord. Br J Neurosurg. 2004;18:548–51. 29. Scheinker IM. Subependymoma: a newly recognized tumor of subependymal derivation. J Neurosurg. 1945;2:232–40. 30. Fu YS, Chen AT, Kay S, Young H. Is subependymoma (subependymal glomerate astrocytoma) an astrocytoma or ependymoma? A comparative ultrastructural and tissue culture study. Cancer. 1974;34:1992–2008.
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31. Moss TH. Observations on the nature of subependymoma: an electron microscopic study. Neuropathol Appl Neurobiol. 1984;10:63–75. 32. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109. 33. Friede RL, Pollak A. The cytogenetic basis for classifying ependymomas. J Neuropathol Exp Neurol. 1978;37:103–18.
CASE REPORT
Intramedullary cervicothoracic subependymoma: report of three cases and review of the literature Zhiwei Wu • Akio Iwanami • Akimasa Yasuda • Shuji Mikami • Yoshiaki Toyama • Masaya Nakamura
Received: 25 November 2013 / Accepted: 1 May 2014 Ó The Japanese Orthopaedic Association 2014
Introduction A subependymoma is a tumor of the central nervous system. It is usually found in an intraventricular location. Most intraventricular subependymomas are subclinical in nature, whereas those located on the spine are inevitably accompanied by myelopathy. Spinal cord subependymomas are extremely rare, however. Here we report three cases of intramedullary subependymoma in the cervicothoracic region, and compare their features and surgical follow-up to previously published cases of this tumor type.
Report of cases Case 1 A 19-year-old male presented with bilateral knee pain that had existed for the past 6 years. He complained of bilateral lower limb weakness, and was not able to walk prior
Z. Wu A. Iwanami A. Yasuda Y. Toyama M. Nakamura (&) Department of Orthopaedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjukuku, Tokyo 160-8582, Japan e-mail: [email protected] Z. Wu Department of Orthopaedic Surgery, The First Affiliated Hospital, Xiamen University, No.55 Zhenhai Road, Siming District, Xiamen 361003, China S. Mikami Department of Pathology, Keio University School of Medicine, Shinanomachi 35, Shinjukuku, Tokyo 160-8582, Japan
to admission. Neurological examination revealed muscle weakness in the left leg, but no sensory disturbance. There were no symptoms of bladder dysfunction or stool incontinence. The Japanese Orthopaedic Association score (JOA score) was 9/11. Preoperative magnetic resonance imaging (MRI) demonstrated a left eccentric intramedullary lesion from C6 to T10, which had a clear margin and was hyperintense on T2-weighted images (Fig. 1a, b) without gadolinium (Gd) enhancement. Ganglioglioma, astrocytoma, and ependymoma were considered in the differential diagnosis. The patient underwent a C6 laminoplasty, C7–T10 laminectomy, and posterior midline myelotomy, and a firm and dark yellowish tumor was revealed. The intraoperative histological diagnosis was low-grade glioma. The mass was enucleated piece by piece from the well-demarcated left eccentric area. A cavitron ultrasonic surgical aspirator (CUSA) was used to debulk the intramedullary tumor. No obvious alterations of the sensory evoked potential (SEP) or the motor evoked potential (MEP) were recorded during the operation. Immunohistochemistry revealed that the tumor cells were positive for glial fibrillary acidic protein (Fig. 1c), S100P, and CD99; dot-like positive for epithelial membrane antigen; partially positive for nestin; and negative for Olig2, NFP-MH, NeuN, and CD34. The MIB1 labeling index was 2.1 % (Fig. 1d). Taken together, these results led to a final diagnosis of subependymoma (WHO grade I). After the resection, the residual tumor was treated with adjuvant radiotherapy. The patient developed severe back pain, muscle weakness in his left leg (MMT grade 3–4), and sensory disturbance (hyperthesia in the trunk region and hypothesia below the knee) around 7 days after surgery. At the time of discharge, the JOA score was 7.5/11. MRI after 41 months revealed no change in the size of the residual tumor.
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Fig. 1 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C6–T7 level. WI weighted images, MRI magnetic resonance imaging. b Axial T2WI MRI showing a multilocular tumor located on the left side of the spinal cord. c Representative section
stained with anti-GFAP antibody. Tumor cells are diffusely positive for GFAP (409). GFAP glial fibrillary acidic protein. d Representative section stained for MIB1 showing a low proliferation index (409)
Case 2
tumor to be firm and dark yellowish. The intraoperative histological diagnosis was low-grade glioma. When the left portion of the tumor was subjected to gross subtotal resection, MEP of the left lower extremity suddenly disappeared, and never recovered after that (Fig. 2c). Therefore, gross total resection was halted; the ventral and right portions of the tumor could not be resected. CUSA was also used for debulking of the intramedullary tumor. The final diagnosis was subependymoma. The patient developed left lower extremity numbness and complained of left shoulder pain during the postoperative period. At the time of discharge, the power grade of the left leg below the hip was 1–3, and the JOA score was 6.5/11. The patient has been followed up for 29 months. No adjuvant radiotherapy was administered. MRI after 28 months revealed no change in the size of the residual tumor.
A 60-year-old female presented with bilateral lower extremity numbness and a walking disability that had existed for 12 months. She complained of right leg pain. Neurological examination revealed motor weakness in the bilateral ankles (MMT grade 4–5). Sensory impairment existed in the dermatome below the L4 level. There were no symptoms of bladder dysfunction or stool incontinence. The JOA score was 9/11 before the operation. MRI demonstrated multiple lesions in the ventral spinal cord from C5 to T2 that had clear margins and were hyperintense on T2-WI (Fig. 2a, b) without Gd enhancement. Toxocariasis canis and subarachnoid cyst were considered in the differential diagnosis. The patient underwent a C6–T1 laminoplasty and a T2 laminectomy. Posterior midline myelotomy showed the
123
Spinal intramedullary subependymoma
Fig. 2 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C5–T2 level. b Axial T2WI MRI showing a multilocular tumor invading the spinal cord from three directions. c Changes in
MEP waveforms during surgery in case 2. R right, L left, TA tibialis anterior, GS gastrocnemius. The amplitude of the control waveform is defined as 100 %
Case 3
There was also an intramedullary syrinx. The patient underwent a C6–T1 laminoplasty and a T2–4 laminectomy, and the tumor revealed by posterior midline myelotomy was firm and white-reddish. The intraoperative histological diagnosis was low-grade glioma. After 50 % of the tumor had been resected, the MEP waveform on the right lower extremity decreased and the procedure was suspended until the waveform recovered. During the final resection of the tumor in the ventral side, the MEP disappeared and never recovered (Fig. 3c). The final diagnosis was subependymoma. After surgery, the patient’s bladder dysfunction improved, but he complained of left shoulder pain postoperatively. At the time of discharge, his right lower
A 49-year-old male presented with back pain of duration 1.5 years. He complained of right lower extremity numbness and a walking disability that had existed for 6 months. Neurological examination revealed motor weakness below the right hip (power of 4/5). Sensory impairment existed in the dermatome below C5. He had frequent bladder dysfunction but no stool incontinence. The JOA score was 6/11 before the operation. MRI revealed a right eccentric lesion in the spinal cord from C6 to T3. The lesion had a clear margin, and was hyperintense on T2-WI (Fig. 3a, b), with partial enhancement after paramagnetic contrast.
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Fig. 3 a Sagittal T2WI MRI showing an intramedullary spinal cord tumor at the C6–T3 level. b Axial T2WI MRI showing a tumor located on the right side of the spinal cord. c Changes in MEP
waveforms during surgery in case 3. R right, L left, TA tibialis anterior, GS gastrocnemius. The amplitude of the control waveform is defined as 100 %
extremity numbness had shown no improvement, the right lower extremity power grade was 2–3, and the JOA score was 5/11. The patient has been followed up for 30 months. No adjuvant radiotherapy was administered. Postoperative MRI revealed residual tumor at the C7–T1 level, and MRI after 28 months revealed no change in the size of the residual tumor.
of intracranial tumors, the incidence of cerebral subependymoma is very low (0.2–0.7 %). The occurrence of spinal subependymoma is also exceedingly rare. To our knowledge, only 69 cases have been described in the literature since the first case was reported by Boykin et al. in [1]. There have been 19 cases [1–13] of tumors in the cervicothoracic region, only 15 of which [2–4, 6, 8–13] were intramedullary in nature. The patients in those cases underwent surgery (not just biopsy). Table 1 summarizes the current three cases along with the ten cases that were documented in detail previously [2, 3, 6, 8, 9, 12, 13]. Since a subependymoma is classified as a benign tumor (WHO grade I), and it usually has a distinct cleavage plane,
Discussion A subependymoma is a rare kind of tumor that can occur throughout the central nervous system. Within the category
123
M
F
F
50
53
28
37
20
33
24
45
Vaquero et al. [6]
Pagni et al. [8]
Salvati et al. [9]
Krishnan et al. [12]
Wu et al. [13]
M
F
M
19
60
49
F
M
M
F
M
C6–T3
C5–T2
C6–T10
C5–T1
C4–T3
C7–T6
C7–T5
C3–T7
C4–T7
C5–T1
C3–T1
C6–T2
C3–T1
Location
STR
PR
STR
GTR
GTR
GTR
GTR
STR
TR
TR
TR
GTR
PR
GTR
a
Surgery
Right lower extremity MEP decreased
Left lower extremity MEP decreased
No change
No description
No description
No description
No description
No description
No description
No description
JOA score 6/11
JOA score 9/11
JOA score 9/11
McCormick grade Ib
McCormick grade II
McCormick grade Ib
McCormick grade II
Grade 3/5 power in right upper limb
Progressive tetraparesis, hypesthesia and sphincter disturbances
Amyotrophy of both hands and gait disturbances
Progressive weakness affecting right limbs
Normal
No description No description
Mild left hemiparesis
Preoperative status
A progressive diminution of amplitude followed by partial recovery on the left
Intraoperative SEP/MEP
JOA score 5/11
JOA score 6.5/11
JOA score 7.5/11
McCormick grade II
McCormick grade III
McCormick grade II
McCormick grade III
No progression of symptoms
Slight improvement
Motility improved in hands but decreased in leg; ataxic gait and inexhaustible clonus
Marked paraparesis
Spasticity and left leg weakness
Marked worsening of posterior column function in left hand and leg
Postoperative status
a
2 years later
TR total resection, GTR gross total resection, STR subtotal resection, PR partial resection, SEP sensory evoked potential, MEP motor evoked potential, JOA Japanese Orthopaedic Association
Present
F
48
Lee et al. [3]
F
44
Salcman et al. [2]
Sex
Age
Authors
Table 1 Intramedullary cervicothoracic subependymoma cases
Spinal intramedullary subependymoma
123
Z. Wu et al. Table 2 MRI findings of cervicothoracic intramedullary subependymomas Author
Age
Sex
MRI Location
T1WI
Lee et al. [3]
48
M
Vaquero et al. [6]
50
F
Intramedullary tumor
Pagni et al. [8]
53
M
Enlargement of the intramedullary mass
T2WI
?GA
Syrinx
ND
Enlargement and increased signal intensity
Salvati et al. [9]
28
M
Intramedullary tumor
Krishnan et al. [12]
37
F
ND
ND
Hyperintense
Mild heterogeneous
Wu et al. [13]
20
F
ND
Mild hypo
Mild hyper
Patchy
ND
33 24
M F
ND ND
Iso Iso
Hyper Mild hyper
No Mildly patchy
ND ND
45
F
ND
Mild hypo
Hyper
No
ND
19
M
Left eccentric
Iso
Hyper
No
(-)
60
F
Ventral multiple
Iso
Hyper
No
(-)
49
M
Right eccentric
Iso
Hyper
Patchy
(?)
Present
ND no description, MRI magnetic resonance imaging, iso isointense
we may anticipate a good clinical outcome after an operation performed with the aid of an operating microscope. While this may be true in other areas of the spinal cord or brain ventricles, it is apparently not the case in the cervicothoracic region. As Table 1 reveals, the conditions of most of the patients with intramedullary subependymoma worsened in the postoperative period, although several patients showed some improvement after a long period of rehabilitation [2, 6, 13]. These less-than-optimal outcomes may be related to the surgeon’s operational skills, or to the vulnerability of the spinal cord in the cervicothoracic region [14]. In all of our cases, tumor resection was performed under MEP/SEP monitoring in accordance with an alarm point (more than 30 % of the control amplitude would be safe) for intraoperative spinal cord monitoring, as proposed by the Japanese Society for Spine Surgery and Related Research [15]. However, applying this procedure did not enable the development of new deficits to be avoided, let alone the achievement of gross total resection. Intriguingly, one of these patients presented new deficits after surgery without any drastic change in the MEP waveform during operation. Therefore, these poor outcomes may also be due to other factors, such as postlaminectomy kyphosis and intramedullary microcirculation. Indeed, the spinal cord vasculature around the cervicothoracic region is not abundant as that around the cervical or lumbar region [14, 16]. Additional case studies may lead to an explanation. For surgical treatment, Jang et al. [17] reported that aggressive surgery for this tumor may cause either worsening of an existing deficit or the development of new deficits. Our outcomes are completely in line with their report. Subtotal resection or even partial resection with duraplasty should be considered for the treatment of subependymoma, especially in the
123
cervicothoracic region. There are also some reports supporting the effectiveness of postoperative radiotherapy [17, 18], although this remains controversial. More experience and a longer follow-up would be required to establish its effectiveness. Subependymomas studied by MRI typically show spinal cord enlargement, are hypointense to isointense on T1WI, hyperintense on T2WI, and occasionally display faint enhancement after Gd injection [10, 11, 13, 17–27]. The MRI findings of all reported intramedullary cervicothoracic subependymomas are shown in Table 2. Our results are consistent with those described in the literature. The eccentric location, the segmental fusiform dilatation of the cord, the high rate of nonenhancement, and the syringomyelia occasionally associated with subependymomas are features that distinguish them from ependymomas, which usually form in the center of the cord and present as a wellenhanced lesion accompanied by a cyst [10, 17, 20, 21, 26, 28]. The intramedullary ependymoma is believed to originate in the wall of the central canal, and is classified as WHO grade II. In contrast, subependymomas may develop into huge masses and compress the cord severely, causing their characteristic eccentric localization, which is not distinguishable on MRI [13]. It is difficult to differentiate a subependymoma from other intramedullary tumors using only MRI. In the three cases reported here, the tumors were located at multiple levels and multilocular in shape, which might be considered characteristics of this tumor type on MRI. The pathogenesis of subependymoma is still controversial. When Scheinker [29] first described this type of tumor in 1945, he proposed that it arises from the subependymal cell plate or the residual periventricular matrix layer. Later, Boykin et al. [1] proposed that it originates from
Spinal intramedullary subependymoma
subependymal astrocytes, and consequently named these tumors subependymal glomerate astrocytomas. Fu et al. [30] used electron microscopy to study a tumor consisting of both ependymoma and subependymoma. They found a similarity of cellular components at the ultrastructural level and concluded that a subependymoma is a variety of ependymoma. In 1984, Moss [31] found cells similar to ependymal glial precursor cells in the adult subependymal cell layer, and concluded that subependymomas were separate entities from ependymomas and astrocytomas. Nagashima et al. [5] proposed that the macroscopic eccentric location of subependymomas suggests that they are derived from the subependymal cell plate. Since the immunohistochemical profile tended to support a glial origin, subependymomas were grouped with low-grade glial tumors [32]. Another theory is that they originate from tanycytes [33]. Tanycytes are normally located in the subependymal zone, and have long processes spanning the pial to the ventricular surface. Ultrastructurally, they show features of both astrocytic and ependymal cells. Occasionally, subependymomas are associated with heterotopic leptomeningeal glial tissue, and they have even been found in identical twins. However, Krishnan et al. [12] noted that a better explanation for their eccentric and subpial locations is that spinal subependymomas may be descended from subpial spinal white matter progenitor cells. In conclusion, the surgical outcomes of treating intramedullary cervicothoracic subependymomas were not satisfactory in these three cases, although the tumors were biologically benign. More reports describing these problematic tumors will help us to better understand their etiology and improve their treatment. Conflict of interest of interest.
The authors declare that they have no conflict
Consent section The patients and/or their families were informed that the data, radiographs, and photographs from their cases would be submitted for publication, and gave their consent.
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