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Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis
Journal of Clinical Neuroscience 22 (2015) 1871–1876
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis I.J. Pomeraniec a, R.F. Dallapiazza a, H.M. Sumner b, M.B. Lopes b, C.I. Shaffrey a, J.S. Smith a,⇑ a b
Department of Neurosurgery, University of Virginia Health System, Post Office Box 800212, Charlottesville, VA 22908, USA Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA
a r t i c l e
i n f o
Article history: Received 6 June 2015 Accepted 20 June 2015
Keywords: Anaplastic ependymoma Extramedullary Intradurual Radiation therapy Spine tumors
a b s t r a c t We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Ependymomas are the most common intradural, intramedullary spinal cord tumor. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, we present the first patient with an intradural, extramedullary spinal ependymoma with an anaplastic grade, who presented with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. 2. Case report An otherwise healthy 23-year-old man presented with a 2 month history of increasing neck and upper back pain, which progressed to severe left shoulder and posterior arm pain. He ⇑ Corresponding author. Tel.: +1 434 243 9331; fax: +1 434 243 1758. E-mail address: [email protected] (J.S. Smith). http://dx.doi.org/10.1016/j.jocn.2015.06.015 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
reported numbness in the left C7 dermatome, involving the shoulder, lateral arm and middle finger. His strength was 4/5 in the left triceps, and his wrist and finger extensors were normal. He had moderate hyperreflexia at the patella and biceps, but no Hoffman’s sign or clonus. He was started on steroids and admitted to the hospital with increasing weakness and difficulty urinating, with a post void residual >200 cm3. MRI of the cervical spine revealed an intradural extramedullary lesion located ventral and to the left of the spinal cord, with severe impingement and greater than 70% canal compromise. There was mild cord edema, and the lesion was isointense on T1-weighted images, heterogeneous on T2-weighted images, and had avid enhancement with gadolinium (Fig. 1A–F). Also noted on the gadolinium-enhanced imaging was extensive leptomeningeal enhancing nodularity focused at C2–C3. Given this, we performed an MRI of the remainder of the neuroaxis. The post-gadolinium MRI of the thoracic and lumbar spine demonstrated multiple foci of leptomeningeal nodularity and enhancement along the conus medullaris and cauda equina (Fig. 1G–J). An MRI of the brain was normal with no notable evidence of intracranial mass or leptomeningeal disease (Fig. 1K–M).
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Fig. 1. Preoperative MRI of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Sagittal and (B, C) axial T2-weighted images of the cervical spine, showing an intradural, extramedullary lesion from C4–C7 with heterogeneous signal. The axial images through C5 and C6 show severe spinal cord compression. (D) Sagittal and (E, F) axial T1-weighted post-gadolinium images, showing avid enhancement of the lesion. Diffuse leptomeningeal enhancement is also noted. (G, H) Sagittal and (I, J) axial T1-weighted post-contrast images of the (G, H) thoracic and (I, J) lumbar spine, showing diffuse leptomeningeal enhancement with focal nodularity. (K–M) Axial T1-weighted post-contrast images of the brain show no lesions and no evidence of leptomeningeal disease.
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The patient underwent a C4–C7 cervical laminoplasty with neuromonitoring. Once the thecal sac was exposed, the dura was opened along the midline and the dentate ligaments were divided. The mass was readily apparent, and appeared dark in color with a soft consistency (Fig. 2). The tumor was very adherent to, and partially enveloped the nerve roots, including those at the exiting C6 level. The preliminary pathology of an intraoperative sample was consistent with a glial tumor, or possible ependymoma. Given this diagnosis, an aggressive tumor debulking was performed with excellent decompression of the spinal cord, and limited residual tumor. There were no changes in neuromonitoring, and the patient tolerated the procedure without incident. A microscopic examination of the cervical spinal cord lesion demonstrated a fibrillary glial neoplasm, characterized by numerous perivascular pseudorosettes, microvascular endothelial proliferation, hyalinized vessels, and focal necrosis (Fig. 3). Mitoses were easily found. The individual tumor cells had round to oval nuclei containing prominent nucleoli. A normal appearing spinal cord parenchyma was present, approximating the tumor. The immunohistochemistry showed expression of glial fibrillary acidic protein and vimentin, confirming a glial neoplasm. Additionally, the scattered tumor cells showed dot-like paranuclear reactivity for epithelial membrane antigen (Fig. 3C) and a membranous staining pattern with CD99 (MIC-2), characteristic of ependymomas. The Ki-67 proliferation index was elevated. The morphologic and immunohistochemical features demonstrated an ependymoma, and the presence of microvascular endothelial proliferation and brisk mitotic activity met the diagnostic criteria for an anaplastic ependymoma of World Health Organization (WHO) Grade III. The postoperative course was unremarkable, his strength improved in his left triceps and arm pain was significantly reduced. However, he continued to have numbness in the left C7 distribution. He was discharged home on postoperative day 3 with a steroid taper.
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Subsequently, he was treated with radiation therapy. He received 36 Gy in 20 fractions to the whole brain, 50.8 Gy in 26 fractions to the cervical spine, 45.4 Gy in 23 fractions to the nodular enhancing areas of this thoracolumbar spine, and 40 Gy in 20 fractions to the rest of his spine. He had follow-up brain and spine imaging at 1, 6 and 12 months postoperatively. His latest MRI at 12 months showed no change in the subtle enhancement of the nodular lesions along the surface of the cervical and thoracic spinal cord, and no change in the mild nodularity along the conus medullaris and cauda equina (Fig. 4). Given the anaplastic grade of this tumor, chemotherapy with monthly intravenous cisplatin and daily cyclophosphamide was recommended. However, he elected to postpone chemotherapy. At the 12 month follow-up he reported that he had returned to his pretreatment status and was back at work full time without restrictions. His only complaint was continued hyperpigmentation over his thoracic and lumbar spine after the radiation therapy. 3. Discussion 3.1. Current theories of how the cell of origin resides outside the central canal Ependymomas account for the majority of all intramedullary tumors and remain the most common tumors of glial origin that are found in the spinal cord [1,2]. Intradural, extramedullary ependymomas are rare, with only 19 primary tumors reported to date. Two of these reports described an additional extradural component [3,4]. Ependymomas are most likely to occur where ependymal cells normally reside. In the spinal cord, ependymomas arise from ependymal cells that line the central canal or its remnants, and in the filum terminale. Rarely, ependymomas can occur outside
Fig. 2. Intraoperative photos and findings for removal of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Exposure and (B) resection of the soft extramedullary spinal cord mass. (C) The resection cavity demonstrating near total debulking with minimal residual adherent to the exiting nerve roots. (D) Final plating of the C4–C7 laminoplasty. This figure is available in colour at www.sciencedirect.com.
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Fig. 3. Histopathology of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Hematoxylin and eosin stained section demonstrating a fibrillary glioma with perivascular pseudorosettes, containing cells with round to oval nuclei and prominent nucleoli (original magnification 40 ). Mitoses are easily found (insert; magnification 200 ). (B) The immunostaining for glial fibrillary acidic protein stains the ependymoma in addition to the approximating spinal cord parenchyma (original magnification 40 ). (C) The immunostaining for epithelial membrane antigen shows dot-like staining in the region of the blepharoplast, a feature that is characteristic of ependymal cells (original magnification 200 ). (D) Immunostaining for the Ki-67 proliferation index demonstrates a brisk proliferation index (original magnification 100 ). This figure is available in colour at www.sciencedirect.com.
Fig. 4. Postradiotherapy MRI after removal of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A–C) Sagittal and (D–F) axial postcontrast T1-weighted images of the (A, D) cervical, (B, E) thoracic, and (C, F) lumbar spine, demonstrating minimal nodular enhancement.
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of the central nervous system, particularly as primary presacral tumors [5], primary central nervous system tumor metastasis or direct extensions to the adjacent tissue [6], or subcutaneous, sacrococcygeal tumors disconnected from the spinal cord [7]. Lacking a unitary understanding of how ependymal cells come to reside in the extramedullary intradural space and evolve into tumors, one common explanation points to heterotopic glial tissue which remains from the neural tube during its closure [8– 10]. Observations of an encapsulated appearance (by pia mater and arachnoid membrane), and an absence of medullary connection, perhaps exemplify invagination of the neuraxis into the extramedullary space [11]. This hypothesis has been similarly proposed for the origin of nasal and sacral gliomas that occur outside of the neuraxis. This process may be analogous to the formation of heterotopic dermoid and epidermoid lesions, and to normal embryologic development of sensory ganglia in the lumbosacral spinal cord [12]. This view has been further supported by reports of extraspinal ependymomas in the subcutaneous tissue over the sacrococcygeal region, the meso-ovarium, the ovary, and the broad ligament, all posited to have arisen from ectopic ependymal cell rests. A more recent case report of ependymal tissue in a peripheral nerve root, described a focus of ectopic ependymal tissue formed during embryonic development [10]. Schuurmans et al. treated simultaneous ependymomas in the cervical and lumbar spine and discovered intracranial extracerebral metastasis 2 years after surgery, without evidence of spinal recurrence [13]. These authors proposed a migration of ependymal tumor from the lumbar to cervical level via cerebrospinal fluid. Another view interprets it as a primary tumor that could have been ectopic and seeded to another spinal level and/or the brain once surgery had occurred [14,15].
3.2. Literature review A review of 19 reported patients with primary spinal, intradural, extramedullary ependymomas reveals an age range of 24–69 years, with a majority of tumors found in female patients (Table 1) [4]. This sex discrepancy was previously thought to be tied to hormonal underpinnings, but a recent trend of male patients, including our patient, does not corroborate this hypothesis [9]. The reported patients include two with extradural components [3,4] and seven WHO Grade III or anaplastic grades [4,13,15–19]. One patient had a benign lesion that showed recurrence at the same level, with an anaplastic grade [14]. Three recurrences of primary tumors have been reported, two at the same level and one at a different level, all of which had anaplastic grades. Metastases were reported in two patients, a benign ependymoma that metastasized to the cerebellum [2], and a WHO Grade III tumor that seeded to the brain [13]. The clinical symptoms upon presentation have been closely linked to the tumor location. The most common location of these primary tumors is the thoracic spine. In the reported patients, five involved the cervical spine [11,13,14,17,18], three in the lumbar spine [11,13,20], and two at multiple levels of the spine [11,13]. Accordingly, commonly reported clinical symptoms include varying severities of limb weakness, urinary disturbance, and gait abnormalities due to posterior column compression. Intradural, extramedullary ependymomas have a characteristic well-circumscribed encapsulated appearance intraoperatively, a finding that is consistent with the MRI appearance, showing homogeneous enhancement after gadolinium administration. A notable exception reported by Graca et al. was an isointense lesion on T1-weighted MRI, that was hyperintense on T2-weighted MRI [21]. Two reported ependymomas with extradural components
Table 1 Reported patients with primary spinal intradural, extramedullary ependymomas Study
Age, years
Sex
Level
Location
Pathology
Comments
Metastatic Present study
23
M
C4–C7
Intradural, extramedullary
Leptomeningeal metastasis
Benzagmount et al., 2008 [14]
31
M
C1–C3
Intradural, extramedullary
Anaplastic/WHO Grade III Benign
Schuurmans et al., 2006 [13]
29
F
C3–C6
Intradural, extramedullary
WHO Grade III
Local Guppy et al., 2011 [4]
50
M
T5–T6
Anaplastic
Kinsman et al., 2011 [18] Iunes et al., 2011 [11]
53 32
M M
De Bonis et al., 2009 [3]
60
F
C5–C7 C2–C3, T5–T11, L2, L4, L5 T9–T10
Extradural, intradural, extramedullary Intradural, extramedullary Intradural, extramedullary
WHO Grade II
Benzagmount et al., 2008 [14] Graca et al., 2006 [21] Cerase et al., 2006 [16] Robles et al., 2005 [15]
31 67 56 47
M F M F
C1–C3 T6–T8 T5 T2 T8
Extradural, intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary
T1–T8 T6–T7 T10–T11 T4–T5 C4–T3 Lumbar T7 T5–T10 T7–T9 T2
Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural,
Benign WHO Grade II Ependymoma Myxopapillary WHO Grade III n/a n/a WHO Grade III WHO Grade II WHO Grade I
Duffau et al., 2000 [9] Payer et al., 1999 [12] Wolfla et al., 1997 [25] Cheng et al., 1996 [22] Katoh et al., 1995 [17] Li et al., 1992 [20] Wagle et al., 1988 [26] Oliver et al., 1981 [19] Gonzalez et al., 1971 [27] Cooper et al., 1951 [8]
43 62 69 47 24 63 41 34 43 40
F F F F F M F F F F
F = female, M = male, n/a = not available, WHO = World Health Organization.
extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary
Extradural – right T5-T6 foramen
Anaplastic WHO Grade II
Anaplastic WHO Grade WHO Grade WHO Grade WHO Grade
Asymptomatic posterior fossa lesion Multiple levels, seeded to brain
II III I III
Multiple levels on initial presentation Extradural – left paravertebral space Recurrence at same level Recurrence at same level New occurrence at different level
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support the view that these ependymomas can be readily confused with meningiomas or nerve sheath tumors [3,4]. The majority of reports have described facile removal of these tumors with no dural attachment, with notable exceptions including the tumors with a thin stalk connection to the spinal cord [18,22], tumors infiltrating the arachnoid membrane [11,21], and highly vascular lesions infiltrating the pia [4,15]. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Of the two prior reports of metastatic disease, one detailed an asymptomatic lesion of the posterior fossa from an initially benign lesion of the cervical spine [14], and the other showed intracranial extracerebral metastasis without evidence of spinal recurrence [13]. Our patient is just below the age range previously reported in the literature, and is a 23-year-old man, unlike the female preponderance of patients reported prior to 2005. Five recent reports have been of male patients [4,11,14,16,18], and there have been two reported metastases of intradural, extramedullary ependymomas with anaplastic grades. Schuurmans et al. reported simultaneous ependymomas in the cervical and lumbar spine [13]. They proposed that the lumbar tumor underwent anaplastic transformation, and that these anaplastic ependymoma cells migrated cranially with cerebrospinal fluid circulation, hence, the cervical subdural metastasis. The authors proposed a similar mechanism, along with a role of spinal surgery, in spreading malignant cells within the subdural space, leading to the development of intracranial metastasis. The second report of metastasis by Benzagmount et al. described metastasis of a benign ependymoma to the cerebellum [14]. Neither of these reports described anaplastic ependymomas with leptomeningeal spread, as in our patient. 3.2.1. Whole spine radiation for anaplastic ependymomas Radiotherapy following gross total resection of anaplastic ependymomas (WHO Grade III) appears to be the standard approach, with reports of 5 and 10 year survival rates of 50–100% [6,23]. There does not appear to be unanimity regarding the radiation field size, but a common technique includes two vertebral bodies above and below the tumor, with or without a boost to the lesion. Craniospinal irradiation (3500 cGy in 18 fractions, with a 1500 cGy boost to the primary site) has typically been reserved for tumors with poorly differentiated features and/or diffuse disease [15,24,28]. For the seven intradural, extramedullary spinal ependymomas with anaplastic grades to reported date, treatment has varied. The use of radiation therapy ranged from none postsurgery, to complete resection with adjunctive radiotherapy, to whole spine radiation [17,19]. Schuurmans et al. employed whole spine radiation consisting of 20 fractions of 1.8 Gy, with a boost to the original tumor locations in the cervical and lumbar spine. The patient showed progression until they experienced painful sensations in the lower extremities, which the authors attributed to postradiation myelopathy. A follow-up MRI at 1 year showed no tumor recurrence [13]. Cerase et al. advocated whole spine radiation, which was refused when their patient experienced a marked clinical improvement after surgery. When the patient’s neurological condition worsened secondary to a recurring tumor 1 year later, whole spine radiotherapy was started but interrupted when the patient’s condition acutely worsened, and they died 1 month later [16]. 4. Conclusion Spinal ependymomas rarely occur as extramedullary tumors. Here, we report a patient with an anaplastic extramedullary
cervical ependymoma that presented with leptomeningeal metastasis throughout the spinal canal. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Balériaux DL. Spinal cord tumors. Eur Radiol 1999;9:1252–8. [2] Mccormick PC, Post KD, Stein BM. Intradural extramedullary tumors in adults. Neurosurg Clin N Am 1990;1:591–608. [3] De Bonis P, Montano N, Cioni B, et al. Primary extramedullary extradural ependymoma of the thoracic spine mimicking a schwannoma. J Neurol Neurosurg Psychiatry 2009;80:579–81. [4] Guppy KH, Hou L, Moes GS, et al. Spinal intradural, extramedullary anaplastic ependymoma with an extradural component: case report and review of the literature. Surg Neurol Int 2011;2:119. [5] Morantz RA, Kepes JJ, Batnitzky S, et al. Extraspinal ependymomas. Report of three cases. J Neurosurg 1979;51:383–91. [6] Wolff M, Santiago H, Duby MM. Delayed distant metastasis from a subcutaneous sacrococcygeal ependymoma. Case report, with tissue culture, ultrastructural observations, and review of the literature. Cancer 1972;30:1046–67. [7] Helwig EB, Stern JB. Subcutaneous sacrococcygeal myxopapillary ependymoma. A clinicopathologic study of 32 cases. Am J Clin Pathol 1984;81:156–61. [8] Cooper IS, Craig WM, Kernohan JW. Tumors of the spinal cord; primary extramedullary gliomas. Surg Gynecol Obstet 1951;92:183–90. [9] Duffau H, Gazzaz M, Kujas M, et al. Primary intradural extramedullary ependymoma: case report and review of the literature. Spine (Phila Pa 1976) 2000;25:1993–5. [10] Moser FG, Tuvia J, Lasalla P, et al. Ependymoma of the spinal nerve root: case report. Neurosurgery 1992;31:962–4 [discussion 964]. [11] Iunes EA, Stávale JN, de Cássia Caldas Pessoa R, et al. Multifocal intradural extramedullary ependymoma. Case report. J Neurosurg Spine 2011;14:65–70. [12] Payer M, Yonekawa Y, Imhof HG. Solitary thoracic intradural extramedullary ependymoma. J Clin Neurosci 1999;6:344–5. [13] Schuurmans M, Vanneste JA, Verstegen MJ, et al. Spinal extramedullary anaplastic ependymoma with spinal and intracranial metastases. J Neurooncol 2006;79:57–9. [14] Benzagmout M, Boujraf S, Oulali N, et al. Intradural extramedullary ependymoma: is there constantly a hormonal relationship? Surg Neurol 2008;70:536–8 [discussion 538]. [15] Robles SG, Saldaña C, Boto GR, et al. Intradural extramedullary spinal ependymoma: a benign pathology? Spine (Phila Pa 1976) 2005;30:E251–4. [16] Cerase A, Venturi C, Oliveri G, et al. Intradural extramedullary spinal anaplastic ependymoma. Case illustration. Neurosurg Spine 2006;5:476. [17] Katoh S, Ikata T, Inoue A, et al. Intradural extramedullary ependymoma. A case report. Spine (Phila Pa 1976) 1995;20:2036–8. [18] Kinsman MJ, Callahan JD, Hattab EM, et al. Extramedullary spinal ependymoma: a diagnostic challenge and review of the literature. Clin Neurol Neurosurg 2011;113:661–4. [19] Oliver B, De Castro A, Sarmiento MA, et al. Dorsal extramedullary ependymoma. Arch Neurobiol (Madr) 1981;44:215–24. [20] Li MH, Holtås S, Larsson EM. MR imaging of intradural extramedullary tumors. Acta Radiol 1992;33:207–12. [21] Graça J, Gültasli N, D’Haene N, et al. Cystic extramedullary ependymoma. AJNR Am J Neuroradiol 2006;27:818–21. [22] Cheng CH, Lee TC, Huang HY, et al. Extramedullary thoracic myxopapillary ependymoma–a case report of a rare tumour. Ann Acad Med Singapore 1996;25:869–72. [23] Halvorsen CM, Kolstad F, Hald J, et al. Long-term outcome after resection of intraspinal ependymomas: report of 86 consecutive cases. Neurosurgery 2010;67:1622–31 [discussion 1631]. [24] Volpp PB, Han K, Kagan AR, et al. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 2007;69:1199–204. [25] Wolfla CE, Azzarelli B, Shah MV. Primary extramedullary ependymoma of the thoracic spine. Case illustration. Cancer 1997;87:643. [26] Wagle WA, Jaufman B, Mincy JE. Intradural extramedullary ependymoma: MRpathologic correlation. J Comput Assist Tomogr 1988;12:705–7. [27] González Feria L, Fernández Martín F, Ginovés Sierra M, et al. Giant dorsal extramedullary ependymoma. Arch Neurobiol (Madr) 1971;34:325–32. [28] Peschel RE, Kapp DS, Cardinale F, et al. Ependymomas of the spinal cord. Int J Radiat Oncol Biol Phys 1983;9:1093–6.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis I.J. Pomeraniec a, R.F. Dallapiazza a, H.M. Sumner b, M.B. Lopes b, C.I. Shaffrey a, J.S. Smith a,⇑ a b
Department of Neurosurgery, University of Virginia Health System, Post Office Box 800212, Charlottesville, VA 22908, USA Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA
a r t i c l e
i n f o
Article history: Received 6 June 2015 Accepted 20 June 2015
Keywords: Anaplastic ependymoma Extramedullary Intradurual Radiation therapy Spine tumors
a b s t r a c t We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Ependymomas are the most common intradural, intramedullary spinal cord tumor. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, we present the first patient with an intradural, extramedullary spinal ependymoma with an anaplastic grade, who presented with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. 2. Case report An otherwise healthy 23-year-old man presented with a 2 month history of increasing neck and upper back pain, which progressed to severe left shoulder and posterior arm pain. He ⇑ Corresponding author. Tel.: +1 434 243 9331; fax: +1 434 243 1758. E-mail address: [email protected] (J.S. Smith). http://dx.doi.org/10.1016/j.jocn.2015.06.015 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
reported numbness in the left C7 dermatome, involving the shoulder, lateral arm and middle finger. His strength was 4/5 in the left triceps, and his wrist and finger extensors were normal. He had moderate hyperreflexia at the patella and biceps, but no Hoffman’s sign or clonus. He was started on steroids and admitted to the hospital with increasing weakness and difficulty urinating, with a post void residual >200 cm3. MRI of the cervical spine revealed an intradural extramedullary lesion located ventral and to the left of the spinal cord, with severe impingement and greater than 70% canal compromise. There was mild cord edema, and the lesion was isointense on T1-weighted images, heterogeneous on T2-weighted images, and had avid enhancement with gadolinium (Fig. 1A–F). Also noted on the gadolinium-enhanced imaging was extensive leptomeningeal enhancing nodularity focused at C2–C3. Given this, we performed an MRI of the remainder of the neuroaxis. The post-gadolinium MRI of the thoracic and lumbar spine demonstrated multiple foci of leptomeningeal nodularity and enhancement along the conus medullaris and cauda equina (Fig. 1G–J). An MRI of the brain was normal with no notable evidence of intracranial mass or leptomeningeal disease (Fig. 1K–M).
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Fig. 1. Preoperative MRI of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Sagittal and (B, C) axial T2-weighted images of the cervical spine, showing an intradural, extramedullary lesion from C4–C7 with heterogeneous signal. The axial images through C5 and C6 show severe spinal cord compression. (D) Sagittal and (E, F) axial T1-weighted post-gadolinium images, showing avid enhancement of the lesion. Diffuse leptomeningeal enhancement is also noted. (G, H) Sagittal and (I, J) axial T1-weighted post-contrast images of the (G, H) thoracic and (I, J) lumbar spine, showing diffuse leptomeningeal enhancement with focal nodularity. (K–M) Axial T1-weighted post-contrast images of the brain show no lesions and no evidence of leptomeningeal disease.
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The patient underwent a C4–C7 cervical laminoplasty with neuromonitoring. Once the thecal sac was exposed, the dura was opened along the midline and the dentate ligaments were divided. The mass was readily apparent, and appeared dark in color with a soft consistency (Fig. 2). The tumor was very adherent to, and partially enveloped the nerve roots, including those at the exiting C6 level. The preliminary pathology of an intraoperative sample was consistent with a glial tumor, or possible ependymoma. Given this diagnosis, an aggressive tumor debulking was performed with excellent decompression of the spinal cord, and limited residual tumor. There were no changes in neuromonitoring, and the patient tolerated the procedure without incident. A microscopic examination of the cervical spinal cord lesion demonstrated a fibrillary glial neoplasm, characterized by numerous perivascular pseudorosettes, microvascular endothelial proliferation, hyalinized vessels, and focal necrosis (Fig. 3). Mitoses were easily found. The individual tumor cells had round to oval nuclei containing prominent nucleoli. A normal appearing spinal cord parenchyma was present, approximating the tumor. The immunohistochemistry showed expression of glial fibrillary acidic protein and vimentin, confirming a glial neoplasm. Additionally, the scattered tumor cells showed dot-like paranuclear reactivity for epithelial membrane antigen (Fig. 3C) and a membranous staining pattern with CD99 (MIC-2), characteristic of ependymomas. The Ki-67 proliferation index was elevated. The morphologic and immunohistochemical features demonstrated an ependymoma, and the presence of microvascular endothelial proliferation and brisk mitotic activity met the diagnostic criteria for an anaplastic ependymoma of World Health Organization (WHO) Grade III. The postoperative course was unremarkable, his strength improved in his left triceps and arm pain was significantly reduced. However, he continued to have numbness in the left C7 distribution. He was discharged home on postoperative day 3 with a steroid taper.
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Subsequently, he was treated with radiation therapy. He received 36 Gy in 20 fractions to the whole brain, 50.8 Gy in 26 fractions to the cervical spine, 45.4 Gy in 23 fractions to the nodular enhancing areas of this thoracolumbar spine, and 40 Gy in 20 fractions to the rest of his spine. He had follow-up brain and spine imaging at 1, 6 and 12 months postoperatively. His latest MRI at 12 months showed no change in the subtle enhancement of the nodular lesions along the surface of the cervical and thoracic spinal cord, and no change in the mild nodularity along the conus medullaris and cauda equina (Fig. 4). Given the anaplastic grade of this tumor, chemotherapy with monthly intravenous cisplatin and daily cyclophosphamide was recommended. However, he elected to postpone chemotherapy. At the 12 month follow-up he reported that he had returned to his pretreatment status and was back at work full time without restrictions. His only complaint was continued hyperpigmentation over his thoracic and lumbar spine after the radiation therapy. 3. Discussion 3.1. Current theories of how the cell of origin resides outside the central canal Ependymomas account for the majority of all intramedullary tumors and remain the most common tumors of glial origin that are found in the spinal cord [1,2]. Intradural, extramedullary ependymomas are rare, with only 19 primary tumors reported to date. Two of these reports described an additional extradural component [3,4]. Ependymomas are most likely to occur where ependymal cells normally reside. In the spinal cord, ependymomas arise from ependymal cells that line the central canal or its remnants, and in the filum terminale. Rarely, ependymomas can occur outside
Fig. 2. Intraoperative photos and findings for removal of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Exposure and (B) resection of the soft extramedullary spinal cord mass. (C) The resection cavity demonstrating near total debulking with minimal residual adherent to the exiting nerve roots. (D) Final plating of the C4–C7 laminoplasty. This figure is available in colour at www.sciencedirect.com.
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Fig. 3. Histopathology of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A) Hematoxylin and eosin stained section demonstrating a fibrillary glioma with perivascular pseudorosettes, containing cells with round to oval nuclei and prominent nucleoli (original magnification 40 ). Mitoses are easily found (insert; magnification 200 ). (B) The immunostaining for glial fibrillary acidic protein stains the ependymoma in addition to the approximating spinal cord parenchyma (original magnification 40 ). (C) The immunostaining for epithelial membrane antigen shows dot-like staining in the region of the blepharoplast, a feature that is characteristic of ependymal cells (original magnification 200 ). (D) Immunostaining for the Ki-67 proliferation index demonstrates a brisk proliferation index (original magnification 100 ). This figure is available in colour at www.sciencedirect.com.
Fig. 4. Postradiotherapy MRI after removal of an anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. (A–C) Sagittal and (D–F) axial postcontrast T1-weighted images of the (A, D) cervical, (B, E) thoracic, and (C, F) lumbar spine, demonstrating minimal nodular enhancement.
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of the central nervous system, particularly as primary presacral tumors [5], primary central nervous system tumor metastasis or direct extensions to the adjacent tissue [6], or subcutaneous, sacrococcygeal tumors disconnected from the spinal cord [7]. Lacking a unitary understanding of how ependymal cells come to reside in the extramedullary intradural space and evolve into tumors, one common explanation points to heterotopic glial tissue which remains from the neural tube during its closure [8– 10]. Observations of an encapsulated appearance (by pia mater and arachnoid membrane), and an absence of medullary connection, perhaps exemplify invagination of the neuraxis into the extramedullary space [11]. This hypothesis has been similarly proposed for the origin of nasal and sacral gliomas that occur outside of the neuraxis. This process may be analogous to the formation of heterotopic dermoid and epidermoid lesions, and to normal embryologic development of sensory ganglia in the lumbosacral spinal cord [12]. This view has been further supported by reports of extraspinal ependymomas in the subcutaneous tissue over the sacrococcygeal region, the meso-ovarium, the ovary, and the broad ligament, all posited to have arisen from ectopic ependymal cell rests. A more recent case report of ependymal tissue in a peripheral nerve root, described a focus of ectopic ependymal tissue formed during embryonic development [10]. Schuurmans et al. treated simultaneous ependymomas in the cervical and lumbar spine and discovered intracranial extracerebral metastasis 2 years after surgery, without evidence of spinal recurrence [13]. These authors proposed a migration of ependymal tumor from the lumbar to cervical level via cerebrospinal fluid. Another view interprets it as a primary tumor that could have been ectopic and seeded to another spinal level and/or the brain once surgery had occurred [14,15].
3.2. Literature review A review of 19 reported patients with primary spinal, intradural, extramedullary ependymomas reveals an age range of 24–69 years, with a majority of tumors found in female patients (Table 1) [4]. This sex discrepancy was previously thought to be tied to hormonal underpinnings, but a recent trend of male patients, including our patient, does not corroborate this hypothesis [9]. The reported patients include two with extradural components [3,4] and seven WHO Grade III or anaplastic grades [4,13,15–19]. One patient had a benign lesion that showed recurrence at the same level, with an anaplastic grade [14]. Three recurrences of primary tumors have been reported, two at the same level and one at a different level, all of which had anaplastic grades. Metastases were reported in two patients, a benign ependymoma that metastasized to the cerebellum [2], and a WHO Grade III tumor that seeded to the brain [13]. The clinical symptoms upon presentation have been closely linked to the tumor location. The most common location of these primary tumors is the thoracic spine. In the reported patients, five involved the cervical spine [11,13,14,17,18], three in the lumbar spine [11,13,20], and two at multiple levels of the spine [11,13]. Accordingly, commonly reported clinical symptoms include varying severities of limb weakness, urinary disturbance, and gait abnormalities due to posterior column compression. Intradural, extramedullary ependymomas have a characteristic well-circumscribed encapsulated appearance intraoperatively, a finding that is consistent with the MRI appearance, showing homogeneous enhancement after gadolinium administration. A notable exception reported by Graca et al. was an isointense lesion on T1-weighted MRI, that was hyperintense on T2-weighted MRI [21]. Two reported ependymomas with extradural components
Table 1 Reported patients with primary spinal intradural, extramedullary ependymomas Study
Age, years
Sex
Level
Location
Pathology
Comments
Metastatic Present study
23
M
C4–C7
Intradural, extramedullary
Leptomeningeal metastasis
Benzagmount et al., 2008 [14]
31
M
C1–C3
Intradural, extramedullary
Anaplastic/WHO Grade III Benign
Schuurmans et al., 2006 [13]
29
F
C3–C6
Intradural, extramedullary
WHO Grade III
Local Guppy et al., 2011 [4]
50
M
T5–T6
Anaplastic
Kinsman et al., 2011 [18] Iunes et al., 2011 [11]
53 32
M M
De Bonis et al., 2009 [3]
60
F
C5–C7 C2–C3, T5–T11, L2, L4, L5 T9–T10
Extradural, intradural, extramedullary Intradural, extramedullary Intradural, extramedullary
WHO Grade II
Benzagmount et al., 2008 [14] Graca et al., 2006 [21] Cerase et al., 2006 [16] Robles et al., 2005 [15]
31 67 56 47
M F M F
C1–C3 T6–T8 T5 T2 T8
Extradural, intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary Intradural, extramedullary
T1–T8 T6–T7 T10–T11 T4–T5 C4–T3 Lumbar T7 T5–T10 T7–T9 T2
Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural, Intradural,
Benign WHO Grade II Ependymoma Myxopapillary WHO Grade III n/a n/a WHO Grade III WHO Grade II WHO Grade I
Duffau et al., 2000 [9] Payer et al., 1999 [12] Wolfla et al., 1997 [25] Cheng et al., 1996 [22] Katoh et al., 1995 [17] Li et al., 1992 [20] Wagle et al., 1988 [26] Oliver et al., 1981 [19] Gonzalez et al., 1971 [27] Cooper et al., 1951 [8]
43 62 69 47 24 63 41 34 43 40
F F F F F M F F F F
F = female, M = male, n/a = not available, WHO = World Health Organization.
extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary extramedullary
Extradural – right T5-T6 foramen
Anaplastic WHO Grade II
Anaplastic WHO Grade WHO Grade WHO Grade WHO Grade
Asymptomatic posterior fossa lesion Multiple levels, seeded to brain
II III I III
Multiple levels on initial presentation Extradural – left paravertebral space Recurrence at same level Recurrence at same level New occurrence at different level
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support the view that these ependymomas can be readily confused with meningiomas or nerve sheath tumors [3,4]. The majority of reports have described facile removal of these tumors with no dural attachment, with notable exceptions including the tumors with a thin stalk connection to the spinal cord [18,22], tumors infiltrating the arachnoid membrane [11,21], and highly vascular lesions infiltrating the pia [4,15]. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Of the two prior reports of metastatic disease, one detailed an asymptomatic lesion of the posterior fossa from an initially benign lesion of the cervical spine [14], and the other showed intracranial extracerebral metastasis without evidence of spinal recurrence [13]. Our patient is just below the age range previously reported in the literature, and is a 23-year-old man, unlike the female preponderance of patients reported prior to 2005. Five recent reports have been of male patients [4,11,14,16,18], and there have been two reported metastases of intradural, extramedullary ependymomas with anaplastic grades. Schuurmans et al. reported simultaneous ependymomas in the cervical and lumbar spine [13]. They proposed that the lumbar tumor underwent anaplastic transformation, and that these anaplastic ependymoma cells migrated cranially with cerebrospinal fluid circulation, hence, the cervical subdural metastasis. The authors proposed a similar mechanism, along with a role of spinal surgery, in spreading malignant cells within the subdural space, leading to the development of intracranial metastasis. The second report of metastasis by Benzagmount et al. described metastasis of a benign ependymoma to the cerebellum [14]. Neither of these reports described anaplastic ependymomas with leptomeningeal spread, as in our patient. 3.2.1. Whole spine radiation for anaplastic ependymomas Radiotherapy following gross total resection of anaplastic ependymomas (WHO Grade III) appears to be the standard approach, with reports of 5 and 10 year survival rates of 50–100% [6,23]. There does not appear to be unanimity regarding the radiation field size, but a common technique includes two vertebral bodies above and below the tumor, with or without a boost to the lesion. Craniospinal irradiation (3500 cGy in 18 fractions, with a 1500 cGy boost to the primary site) has typically been reserved for tumors with poorly differentiated features and/or diffuse disease [15,24,28]. For the seven intradural, extramedullary spinal ependymomas with anaplastic grades to reported date, treatment has varied. The use of radiation therapy ranged from none postsurgery, to complete resection with adjunctive radiotherapy, to whole spine radiation [17,19]. Schuurmans et al. employed whole spine radiation consisting of 20 fractions of 1.8 Gy, with a boost to the original tumor locations in the cervical and lumbar spine. The patient showed progression until they experienced painful sensations in the lower extremities, which the authors attributed to postradiation myelopathy. A follow-up MRI at 1 year showed no tumor recurrence [13]. Cerase et al. advocated whole spine radiation, which was refused when their patient experienced a marked clinical improvement after surgery. When the patient’s neurological condition worsened secondary to a recurring tumor 1 year later, whole spine radiotherapy was started but interrupted when the patient’s condition acutely worsened, and they died 1 month later [16]. 4. Conclusion Spinal ependymomas rarely occur as extramedullary tumors. Here, we report a patient with an anaplastic extramedullary
cervical ependymoma that presented with leptomeningeal metastasis throughout the spinal canal. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Balériaux DL. Spinal cord tumors. Eur Radiol 1999;9:1252–8. [2] Mccormick PC, Post KD, Stein BM. Intradural extramedullary tumors in adults. Neurosurg Clin N Am 1990;1:591–608. [3] De Bonis P, Montano N, Cioni B, et al. Primary extramedullary extradural ependymoma of the thoracic spine mimicking a schwannoma. J Neurol Neurosurg Psychiatry 2009;80:579–81. [4] Guppy KH, Hou L, Moes GS, et al. Spinal intradural, extramedullary anaplastic ependymoma with an extradural component: case report and review of the literature. Surg Neurol Int 2011;2:119. [5] Morantz RA, Kepes JJ, Batnitzky S, et al. Extraspinal ependymomas. Report of three cases. J Neurosurg 1979;51:383–91. [6] Wolff M, Santiago H, Duby MM. Delayed distant metastasis from a subcutaneous sacrococcygeal ependymoma. Case report, with tissue culture, ultrastructural observations, and review of the literature. Cancer 1972;30:1046–67. [7] Helwig EB, Stern JB. Subcutaneous sacrococcygeal myxopapillary ependymoma. A clinicopathologic study of 32 cases. Am J Clin Pathol 1984;81:156–61. [8] Cooper IS, Craig WM, Kernohan JW. Tumors of the spinal cord; primary extramedullary gliomas. Surg Gynecol Obstet 1951;92:183–90. [9] Duffau H, Gazzaz M, Kujas M, et al. Primary intradural extramedullary ependymoma: case report and review of the literature. Spine (Phila Pa 1976) 2000;25:1993–5. [10] Moser FG, Tuvia J, Lasalla P, et al. Ependymoma of the spinal nerve root: case report. Neurosurgery 1992;31:962–4 [discussion 964]. [11] Iunes EA, Stávale JN, de Cássia Caldas Pessoa R, et al. Multifocal intradural extramedullary ependymoma. Case report. J Neurosurg Spine 2011;14:65–70. [12] Payer M, Yonekawa Y, Imhof HG. Solitary thoracic intradural extramedullary ependymoma. J Clin Neurosci 1999;6:344–5. [13] Schuurmans M, Vanneste JA, Verstegen MJ, et al. Spinal extramedullary anaplastic ependymoma with spinal and intracranial metastases. J Neurooncol 2006;79:57–9. [14] Benzagmout M, Boujraf S, Oulali N, et al. Intradural extramedullary ependymoma: is there constantly a hormonal relationship? Surg Neurol 2008;70:536–8 [discussion 538]. [15] Robles SG, Saldaña C, Boto GR, et al. Intradural extramedullary spinal ependymoma: a benign pathology? Spine (Phila Pa 1976) 2005;30:E251–4. [16] Cerase A, Venturi C, Oliveri G, et al. Intradural extramedullary spinal anaplastic ependymoma. Case illustration. Neurosurg Spine 2006;5:476. [17] Katoh S, Ikata T, Inoue A, et al. Intradural extramedullary ependymoma. A case report. Spine (Phila Pa 1976) 1995;20:2036–8. [18] Kinsman MJ, Callahan JD, Hattab EM, et al. Extramedullary spinal ependymoma: a diagnostic challenge and review of the literature. Clin Neurol Neurosurg 2011;113:661–4. [19] Oliver B, De Castro A, Sarmiento MA, et al. Dorsal extramedullary ependymoma. Arch Neurobiol (Madr) 1981;44:215–24. [20] Li MH, Holtås S, Larsson EM. MR imaging of intradural extramedullary tumors. Acta Radiol 1992;33:207–12. [21] Graça J, Gültasli N, D’Haene N, et al. Cystic extramedullary ependymoma. AJNR Am J Neuroradiol 2006;27:818–21. [22] Cheng CH, Lee TC, Huang HY, et al. Extramedullary thoracic myxopapillary ependymoma–a case report of a rare tumour. Ann Acad Med Singapore 1996;25:869–72. [23] Halvorsen CM, Kolstad F, Hald J, et al. Long-term outcome after resection of intraspinal ependymomas: report of 86 consecutive cases. Neurosurgery 2010;67:1622–31 [discussion 1631]. [24] Volpp PB, Han K, Kagan AR, et al. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 2007;69:1199–204. [25] Wolfla CE, Azzarelli B, Shah MV. Primary extramedullary ependymoma of the thoracic spine. Case illustration. Cancer 1997;87:643. [26] Wagle WA, Jaufman B, Mincy JE. Intradural extramedullary ependymoma: MRpathologic correlation. J Comput Assist Tomogr 1988;12:705–7. [27] González Feria L, Fernández Martín F, Ginovés Sierra M, et al. Giant dorsal extramedullary ependymoma. Arch Neurobiol (Madr) 1971;34:325–32. [28] Peschel RE, Kapp DS, Cardinale F, et al. Ependymomas of the spinal cord. Int J Radiat Oncol Biol Phys 1983;9:1093–6.