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primitive neuroectodermal tumors
Journal of Clinical Neuroscience 18 (2011) 601–606
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Review
Intraspinal Ewing’s sarcoma/primitive neuroectodermal tumors Yong Yan , Tao Xu , Juxiang Chen ⇑, Guohan Hu, Yicheng Lu Department of Neurosurgery, Changzheng Hospital, Neurosurgery Research Institution of Shanghai, 415 Fengyang Street, Huangpu District, Shanghai 200003, China
a r t i c l e
i n f o
Article history: Received 13 August 2010 Accepted 22 September 2010
Keywords: Ewing’s sarcoma Intradural–extramedullary spinal cord neoplasms Intramedullary spinal cord neoplasms Malignant spinal cord neoplasms Primitive neuroectodermal tumors
a b s t r a c t Intraspinal Ewing’s sarcoma (ES) and primitive neuroectodermal tumors (PNET) are very rare, and the characteristics and prognoses of the disease remain unclear. We present an illustrative patient with an intradural, extramedullary PNET arising within the cervical spinal canal, with clinical and radiological manifestations of leptomeningeal spread, and review the reports of a further 77 patients with intraspinal ES/PNET. Cox regression analyses showed that tumor location (extradural, intradural) (p = 0.002, RR = 4.217, 95% confidence interval [CI] 1.668–10.664) and spinal segment location (cervical, thoracic, lumbar, or sacral) (p = 0.017, RR = 2.040, 95% CI 1.133–3.673) were independent factors in the prognosis of intraspinal ES/PNET. We concluded that a peripheral PNET may originate within the spinal canal and exhibit leptomeningeal spread similar to that seen in central PNET, and that a patient with an intradural ES/PNET high in the spinal canal is more likely to have a poor prognosis. Ó 2010 Published by Elsevier Ltd.
1. Introduction Ewing’s sarcoma (ES) and primitive neuroectodermal tumors (PNET) have been defined as two separate diseases occurring at different sites with different origins. ES was thought to be a malignant tumor originating from marrow mesenchymal stem cells and was predisposed to growing in the extremities, whereas PNET signified all embryonal tumors of the central nervous system (CNS), regardless of their sites of origin.1,2 ES and PNET had similar histologic appearances, consisting of monomorphic, undifferentiated, small, round, hyperchromatic cells. With the finding that ES also occurred in soft tissue (extraskeletal ES), and that tumors outside the CNS were derived from the neural crest (peripheral PNET), the definitions of ES and PNET began to overlap.3 Accordingly, PNET derived in the CNS was named central PNET (cPNET) to differentiate it from peripheral PNET (pPNET).4 Cytogenetic analysis detected the presence of a reciprocal translocation t(11;22)(q24;q12) or t(21;22)(q22;q12) with high frequency (up to 95%) in both pPNET and ES, whereas this translocation was not detected in cPNET.4,5 Fusion genes led to the abnormal expression of a series of polypeptides or proteins, with the most common being CD99. Immunoreactivity to CD99 was present in extraskeletal ES and peripheral PNET, but absent in central PNET. Therefore, ES and pPNET represented two ends of the spectrum of the same tumoral entity, with diverse degrees of histological differentiation. pPNET displayed many properties
⇑ Corresponding author. Tel.: +86 21 81885673.
E-mail address: [email protected] (J. Chen). The first two authors contributed equally to the article.
0967-5868/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.jocn.2010.09.012
of neurogenic tumors, including positive immunoreactivity for neuronal markers (neuron-specific enolase [NSE] and synaptophysin [syn]), light microscopic evidence of Homer-Wright rosettes, and ultrastructural evidence of neuronal differentiation (interdigitating cell processes and neurosecretory granules).6,7 ES did not display such differentiated properties. Therefore, ES was considered to be the least differentiated, and pPNET was the most differentiated member of the ES family.8 Intraspinal ES/PNET is rare, and the characteristics and prognosis of the disease remain unclear. Our literature search revealed reports of 78 patients with ES/PNET located within the spinal canal,3,4,9–58 and we discuss the clinical characteristics, factors affecting prognosis, and treatment choices of the disease. In addition, we present an illustrative patient with an intradural, extramedullary pPNET arising within the cervical spinal canal that was associated with a rapidly deteriorating clinical course and poor prognosis.
2. Illustrative patient A 10-year-old Chinese boy presented with a 20-day history of neck pain and worsening muscle weakness, as well as a 1-week history of dysuria. Neurological examination revealed bilateral hypoesthesia in the upper limbs and paralysis of the extremities, with 2/5 strength in the right arm, 3/5 strength in the right leg, and 4/5 strength in the left limbs. The patient was also found to have flaccid muscle tone and reduced tendon reflexes in the right arm. The patient’s MRI scan revealed an extramedullary mass to the right of C2–C3, causing severe compression of the spinal cord. The
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mass measured 3.0 cm by 2.0 cm by 1.5 cm and had long T1weighted and T2-weighted signals on MRI, with homogeneous and intermediate post-contrast enhancement. An unusual feature was pial enhancement, extending above the tumor (Fig. 1). There was no clinical or radiologic evidence of cerebellar medulloblastoma or other intracranial tumors. A laminectomy was performed to decompress the spinal cord and debulk the tumor. A grey-reddish colored, well-circumscribed lesion with moderate blood supply and intact pseudocapsule was found on the opening of the spinal dura (Supplementary Fig. 1). The lesion was closely related to the cervical nerves, with no extension to the dura matter or spinal cord. The tumor was totally removed via bolck resection. Muscle strength in the extremities improved to 5/5 after surgery. The boy had urinary difficulty on the first few days after surgery, but soon recovered to normal. Unfortunately, the child’s condition deteriorated. He developed dizziness and nausea, hearing loss, facial paralysis, oculomotor nerve paralysis, seizures, and limb movement disturbance. Seeding metastasis of the tumor into the cerebrospinal fluid (CSF) was suspected; however, no tumor cells were detected on CSF cytological analysis. There were, however, many lymphocytes. The child was transferred to another hospital to receive radiation treatment; however, he died just before the radiation could be given. It was approximately 30 days after surgery. The tumor had a tough texture and a gray-white cut-surface macroscopically. Microscopically, the tumor was composed of diffuse solid sheets of small cells with scanty cytoplasm, round–oval nuclei, inconspicuous nucleoli, and fine chromatin. Rosettes were present (Supplementary Fig. 2a). The tumor cells were strongly positive for CD99 (Supplementary Fig. 2b), weakly positive for vimentin, and negative for syn, cytokinin, desmin, glial fibrillary acidic protein, leucocyte common antigen, neurofilament protein, NSE, S-100, actin, myogenic differentiation antigen 1, chromogranin A, myeloperoxidase, terminal deoxynucleotidyl transferase, and lymphoid markers (including CD19, CD5, CD10, CD20, CD2, CD117, CD79a, CD3, and CD34). The immunohistochemical characteristics were consistent with pPNET. 3. Review of the literature We found a total of 78 patients with intraspinal PNET (55) and ES (23) in the literature (Table 1). Survival time, and variables
including age (615, 16–30, 31–60, P61 years), sex (male, female), resection extent (biopsy, partial resection, subtotal or total resection), spinal level (lumbar and sacral, thoracic, cervical), tumor location (extradural, intradural), radiotherapy (yes, no), chemotherapy (yes, no), and pathology (PNET, ES) were collected to perform Cox regression analysis on the prognostic factors of these 78 patients with intraspinal ES/PNET. Calculations were done using the Statistical Package for the Social Sciences version 17.0 (SPSS, Chicago, IL, USA). 3.1. Cox regression analysis of prognostic factors From the available data (Table 1), we found that ES/PNET is more likely to occur in males (male/female = 1.8849/26) and young people (age < 25 years/P25 years = 2.052/26). It was more likely to occur in the lower spinal canal than in the upper (cervical [n = 19, 24.7%], thoracic [n = 25, 32.5%], lumbar and sacral [n = 33, 42.9%]). Most tumors (n = 70, 89.7%) occurred in the extradural space (extradural [n = 31, 44.3%], cauda equina [n = 13, 18.6%], extramedullary [n = 12, 17.1%], intra–extramedullary [n = 5, 7.1%], and intramedullary [n = 9, 2.9%]). ES was more common extradurally (n = 17, 85.0%), and PNET was more common intradurally (n = 37, 74.5%). Cervical extramedullary PNET was rare: to our knowledge, only four patients have been reported. Leptomeningeal spread of the tumor was common in cPNET, but rare in pPNET. To our knowledge, ours is the first report of pPNET with leptomeningeal spread. Cox regression analysis showed that tumor location (p = 0.002, RR = 4.217, 95% confidence interval [CI] 1.668–10.664) and spinal cord level (p = 0.017, RR = 2.040, 95% CI 1.133–3.673) were independent factors in the prognosis of spinal ES/PNET patients. Thus, patients with intradural and high spinal cord level ES/PNET have a poor prognosis. 3.2. Clinical features Given the clinical differences seen in cPNET and pPNET, it is necessary to separate the two. Although both cPNET and pPNET are aggressive tumors, pPNET is known to be metastatic and invasive, while cPNET rarely metastasizes outside the CNS.4 An interesting finding in our patient is the unusual pial enhancement. On close examination, the pial enhancement extended inferiorly to the cervical–thoracic junction and posteriorly and superiorly to the ventral medulla and pons (Fig. 1), which suggests that a pPNET
Fig. 1. Post-contrast MRI of a 10-year-old Chinese boy: (a) sagittal T1-weighted MRI showing a moderately enhanced lesion in the intradural and extramedullary space at the C2–C3 level; and (b) coronal T1-weighted MRI showing unusual pial enhancement extending superiorly, involving the ventral medulla and pons, and extending inferiorly as far as the cervicothoracic junction, particularly posteriorly.
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Y. Yan et al. / Journal of Clinical Neuroscience 18 (2011) 601–606 Table 1 Reports of patients with spinal Ewing’s sarcoma (ES)/primitive neuroectodermal tumors (PNET). Yearref 9
1969 197810 197810 197810 198511 198511 198511 198712 198713 198814 198814 198915 199116 199217 199217 199217 199217 199217 199217 199217 199218 199319 199319 199420 199421 199622 199623 199623 199724 199725 199826 199827 199928 199928 199929 199930 200031 200032 200133 200134 200134 200134 200134 200134 200135 200236 200237 200238 200339 200339 20032 20032 20032 20032 200440 200441 200442 200443 200544 200645 20064 200646 200647 200648 200749 200749 200749 200750 200750 200751 200852 200853 200854 200855
Age/sex
Level
Location
Treatment
Survival (m)
Diagnosis
24 y/M <10 y/N.A. <10 y/N.A. <10 y/N.A. 24 y/M 56 y/M 39 y/M 26 y/F 26 y/M 26 y/M 15 y/F 7 y/M 7 y/M 21 y/F 13 y/F 23 y/M 24 y/M 16 y/M 12 y/M 22 y/F 16 y/F 17 y/M 11 m/M 47 y/M 41 y/M 3 m/F 7 y/F 14 y/M 14 y/F 14 y/M 23 y/F 2 y/F 32 y/M 17 y/M 16 y/M 7 y/F 52 y/M 12 y/F 13 y/F 29 y/F 18 y/M 22 y/M 31 y/M 13 y/M 21 y/M 69 y/M 5 y/M 18 y/F 49 y/F 29 y/F 12 y/F 10 y/M 30 y/F 14 y/M 17 y/M 31 y/M 16 y/M 26 y/M 37 y/M 70 y/M 2 y/M 38 y/M 54 y/F 28 y/F 8 y/M 9 y/M 18 y/M 27 y/M 16 y/F 19 y/F 4 y/F 27 y/M 13 y/F 12 y/M
L C C TL L4–5 L2–3 L L4–Sa1 C2–3 T1–5, L3–4 T8–L2 T4–Sa3 L1–2 C4–5 T10 T10 L1 L3 L3 L5–Sa1 L2 L4–Sa1 C5–T1 L3–Sa1 T T7–L5 L5–Sa1 L4–5 T12–L1 T12–L1 T9–10 C1–C6 Sa1 L3–5 N.A. L5–Sa1 L2–5 C7–T4 C7–T11 C3–5 T8 L5–Sa1 L3–4 C3–5 T10–11, L1–2 C7–T3 C7–T1 L3–5 L2 T2, T10–11 T1–3 C6–T3 C2–4 L1–2 T11–L2 LS T8–9 L1 L L4–Sa1 C2–6 T1–3 C2–5 L C2–4 T9–L1 C–T L4–5 L2–Sa1 T11–L2 T11–L3/4 Sa1–2 L T7–9
CE N.A. N.A. N.A. CE CE CE Extradural Extramedullary Intra–extramedullary Intra–extramedullary Intramedullary Extradural Extradural Extradural Extradural Extradural Extradural Extradural Extradural Intramedullary Extradural N.A. CE Extramedullary Intramedullary N.A. N.A. Intramedullary CE Extramedullary Intra–extramedullary Extradural Extradural N.A. CE CE Extradural Extradural Extradural Extradural Extradural Extradural Extradural Intra–extramedullary Intra–extramedullary Extradural Extramedullary CE Intramedullary Extradural Extradural Extramedullary Extramedullary Intramedullary CE Extradural Extradural Extramedullary CE Intramedullary Intramedullary Intramedullary Extradural Extradural Extramedullary Intramedullary Extradural CE Extramedullary Extradural CE Extradural Extradural
S, RT S, RT, CT N.A. N.A. S (TR), RT S, RT S, RT S, RT S(TR), RT S, RT S, RT, CT Biopsy, CT, RT S(PR), CT S(TR), CT Biopsy, RT, CT S(TR), RT, CT S(TR), RT, CT S(subTR), RT, CT S(subTR), RT, CT S(PR), RT, CT N.A. S(PR), RT, CT S(subTR), RT, CT Biopsy, RT, CT N.A. Biopsy, RT, CT RT, S(subTR), CT S(subTR), CT S(TR), CT, RT N.A. S(subTR), RT, CT S, RT S(TR), RT, CT S(TR), CT, RT N.A. S(PR), CT, RT S(PR), RT Biopsy, RT Biopsy, CT, RT S(PR), CT, RT S(PR), CT, RT Biopsy, CT, RT S(PR), CT, RT S(PR), CT, RT S(TR), RT, CT S(PR), RT S(TR), RT S(PR), CT, RT S(TR), RT, CT Biopsy, RT, CT S(PR), CT, RT S(PR), CT, RT S(PR), CT, RT S(TR), CT, ASCR S(STR), RT S, RT, CT S(TR), RT, CT S(TR), CT, RT S(PR), RT S(PR), RT, CT Biopsy Biopsy, CT S(PR), RT S, RT, CT S(TR) S(subTR), RT, CT Biopsy, RT, CT S(TR), CT, RT S(PR), CT, RT S(TR), RT, CT, ASCR S(subTR), RT, CT S(TR), RT, CT N.A. S(TR), CT, RT
10 <24 <24 <24 18 Alive at 36 42 Alive at 6 10 d 36 18 20 Alive at 40 Alive at 6 Alive at 10 y 7 10 >2 6.5 y <14 29 Alive at 7 y Alive at 2 y 16 Alive at 36 0.5 Alive, in remission 8 Alive at 15 Alive at 3 Alive at 12 Several d 29 Alive at 23 N.A. 18 Alive at 12 Alive at 4 Alive at 31 Alive at 30 Alive at 18 Alive at 15 Alive at 32 Alive at 11 Alive at 30 3 Alive at 8 Alive at 25 23 17 32 22 14 Alive at 67 Alive at 4 2 Alive at 7 Alive at 17 6 Alive at 12 7d 18 N.A. Alive at 24 Recurrent at 8 Alive at 18 Alive at 6 Alive at 72 Alive at 5 Alive at 24 Alive at 22 Alive at 24 N.A. Alive at 20
PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET ES ES ES ES ES ES ES ES PNET ES ES PNET PNET PNET ES ES PNET PNET PNET PNET pPNET pPNET PNET ES pPNET Infected ES pPNET ES ES ES ES ES ES PNET PNET PNET pPNET PNET ES PNET PNET PNET pPNET pPNET PNET PNET PNET pPNET cPNET PNET cPNET pPNET PNET PNET PNET pPNET pPNET pPNET ES PNET PNET ES
(continued on next page)
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Table 1 (continued) Yearref
Age/sex
Level
Location
Treatment
Survival (m)
Diagnosis
200856 200957 201058 Illustrative patient
24 y/M 29 y/M 45 y/M 10 y/M
T, TL T9–10 C3–5 C2–3
Extradural Extramedullary Extramedullary Extramedullary
S, RT S(PR), CT S(subTR) S(TR)
Alive at 12 4 13 1
pPNET pPNET pPNET pPNET
ASCR = Autologous stem cell rescue, C = cervical, CE = Cauda equina, C–T = cervicothoracic, CT = chemotherapy, d = days, F = female, L = lumbar, LS = lumbosacral, m = month, M = male, N.A. = not available, PR = partial resection, RT = radiotherapy, Sa = Sacral, subTR = subtotal resection, S = surgery, T = thoracic, TL = thoracolumbar, TR = total resection, y = year.
Fig. 2. Postoperative MRI at (a, c, e) 10 days, and (b, d, f) 20 days after surgery showing pathologic changes of the posterior fossa contents: (a, b), sagittal post-contrast T1weighted MRI showing swelling of the posterior fossa contents and narrowing of the cerebrospinal fluid effluent passage – the pia matter enhancement was more extensive and obvious in (b); (c, d) axial post-contrast T1-weighted MRI showing swelling of the vestibulocochlear and facial nerves signified by the increase in abnormal signals in the cerebellopontine angles; and (e, f) axial T2-weighted MRI showing increased subpial edema of the cerebellar cortex (f), leading to swelling of the cerebellum.
may originate within the spinal canal and exhibit leptomeningeal spread similar to that seen in cPNET. Most spinal ES/PNET lesions demonstrate the following clinical characteristics: a space occupying lesion with neural compression as the main clinical symptom; long T1-weighted and T2-weighted signals on MRI, with some enhancement of the solid component of
the tumor post-contrast. The mass is usually well circumscribed, is generated from the meninges and cauda equina, infiltrates the neural foramen, and encases spinal nerves and vascular structures:4,45,47,58,59 all of which were found in the illustrative patient. Our patient temporarily improved during the first week after surgery, but shortly thereafter, he developed dizziness, nausea, and
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symptoms involving cranial nerves III, VII, and VIII. Subsequent MRI scans revealed subpial edema on the surface of the cerebral peduncle, pons, medulla oblongata, and cerebellum, indicating leptomeningeal spread of the tumor cells to these sites (Fig. 2a, b, e, f). Cranial nerves in the cerebellopontine angle swelled, which could explain the hearing loss and facial paralysis (Fig. 2b, c). Increasing edema caused the posterior contents to swell and obstruct the CSF effluent passages (Fig. 2a, b, e, f). Despite insertion of a shunt to release the obstructive hydrocephalus, the child died within a few days before any adjunctive therapy could be given. All the symptoms mentioned above are closely related to the leptomeningeal spread of the tumor cells, which is very rare in pPNET. 3.3. Treatment options The treatment for ES/PNET includes surgical resection, irradiation, and chemotherapy.60 The significance of surgical resection lies first in the confirmation of the diagnosis. Lacking clinical and radiographic specificity, it is often difficult to differentiate ES/PNET from other diseases in the spinal canal, including schwannoma, meningioma and glioma; therefore, a pathological examination after surgery is essential for diagnosis. Second, reducing the tumor volume by surgical resection is the basis for other adjuvant treatments, including radiotherapy and chemotherapy. It has been reported that post-operative irradiation has a better effect than irradiation alone.61,62 Radiotherapy includes local irradiation and neuroaxis irradiation, and the choice between the two methods depends on the general condition of the patient and the nature of the disease. Chemotherapy is another choice. The combination of ifosfamide and etoposide, in conjunction with vincristine, doxorubicin and cyclophosphamide based therapy, has significantly improved response rates and survival in patients with ES/PNET.59,62–64 However, in intrathecal ES/PNET, the blood–brain barrier prevents chemotherapeutic agents from gaining access to the tumor. Categories of agents suitable for intrathecal injection are very limited, and most of these agents are not suitable for the tumor. Therefore, intrathecal ES/PNET is difficult to treat. In our patient, the rapid progression of the disease precluded further treatment. The poor prognosis is partly related to the nature of the disease, and partly to our unfamiliarity with it. A more detailed understanding of intraspinal ES/PNET may allow better treatment options for this rare disease. Acknowledgements This study was supported by a grant from China 863 Project (2007AA02Z483) and the National Natural Science Foundation (30772247). We also thank Dr Xiaojun Wu and Dr Tao Wang for their clinical work. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2010.09.012. References 1. Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer 1973;32:890–7. 2. Rorke LB. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983;42:1–15. 3. Harimaya K, Oda Y, Matsuda S, et al. Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 2003;28:E408–12. 4. Kampman WA, Kros JM, De Jong TH, et al. Primitive neuroectodermal tumours (PNETs) located in the spinal canal; the relevance of classification as central or peripheral PNET: case report of a primary spinal PNET occurrence with a critical literature review. J Neurooncol 2006;77:65–72.
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40. Kim YW, Jin BH, Kim TS, et al. Primary intraspinal primitive neuroectodermal tumor at conus medullaris. Yonsei Med J 2004;45:533–8. 41. Akyuz M, Demiral AN, Gurer IE, et al. Primary primitive neuro-ectodermal tumor of cauda equina with intracranial seeding. Acta Neurochir (Wien) 2004;146:525–8. 42. Aydin MV, Sen O, Ozel S, et al. Primary primitive neuroectodermal tumor within the spinal epidural space: report of a case and review of the literature. Neurol Res 2004;26:774–7. 43. Weber DC, Rutz HP, Lomax AJ, et al. First spinal axis segment irradiation with spot-scanning proton beam delivered in the treatment of a lumbar primitive neuroectodermal tumour: case report and review of the literature. Clin Oncol (R Coll Radiol) 2004;16:326–31. 44. Bohn Sarmiento U, Aguiar Bujanda D, Camacho Galan R, et al. Lumbar region intra-spinal primitive neuroectodermal tumour (PNET) combined with neurofibromatosis type 1. Clin Transl Oncol 2005;7:464–7. 45. Fabre E, Guillevin R, Chretien F, et al. Peripheral primitive neuroectodermal tumor of the cauda equina in an elderly patient. Case report. J Neurosurg Spine 2006;5:68–71. 46. De Tommasi A, De Tommasi C, Occhiogrosso G, et al. Primary intramedullary primitive neuroectodermal tumor (PNET) – case report and review of the literature. Eur J Neurol 2006;13:240–3. 47. Jain A, Jalali R, Nadkarni TD, et al. Primary intramedullary primitive neuroectodermal tumor of the cervical spinal cord. Case report. J Neurosurg Spine 2006;4:497–502. 48. Koudelova J, Kunesova M, Koudela Jr K, et al. Peripheral primitive neuroectodermal tumor – PNET. Acta Chir Orthop Traumatol Cech 2006;73:39–44. 49. Kumar R, Reddy SJ, Wani AA, et al. Primary spinal primitive neuroectodermal tumor: case series and review of the literature. Pediatr Neurosurg 2007;43:1–6. 50. Perry R, Gonzales I, Finlay J, et al. Primary peripheral primitive neuroectodermal tumors of the spinal cord: report of two cases and review of the literature. J Neurooncol 2007;81:259–64. 51. Nutman A, Postovsky S, Zaidman I, et al. Primary intraspinal primitive neuroectodermal tumor treated with autologous stem cell transplantation: case report and review of the literature. Pediatr Hematol Oncol 2007;24:53–61.
52. Song X, Choi J, Rao C, et al. Primary Ewing sarcoma of lumbar spine with massive intraspinal extension. Pediatr Neurol 2008;38:58–60. 53. Musahl V, Rihn JA, Fumich FE, et al. Sacral intraspinal extradural primitive neuroectodermal tumor. Spine J 2008;8:1024–9. 54. Ozdemir N, Usta G, Minoglu M, et al. Primary primitive neuroectodermal tumor of the lumbar extradural space. J Neurosurg Pediatr 2008;2:215–21. 55. Hsieh CT, Chiang YH, Tsai WC, et al. Primary spinal epidural Ewing sarcoma: a case report and review of the literature. Turk J Pediatr 2008;50:282–6. 56. Feng JF, Liang YM, Bao YH, et al. Multiple primary primitive neuroectodermal tumours within the spinal epidural space with non-concurrent onset. J Int Med Res 2008;36:366–70. 57. Hrabalek L, Kalita O, Svebisova H, et al. Dumbbell-shaped peripheral primitive neuroectodermal tumor of the spine – case report and review of the literature. J Neurooncol 2009;92:211–7. 58. Alexander HS, Koleda C, Hunn MK. Peripheral primitive neuroectodermal tumour (pPNET) in the cervical spine. J Clin Neurosci 2010;17:259–61. 59. Ali S, Mackenzie K, Reid R, et al. Cervical extraskeletal Ewing’s sarcoma: case report demonstrating radiological features and management. J Laryngol Otol 2008;122:998–1001. 60. Al-Najar A, Siggelkow M, Naumann CM, et al. Ewing’s sarcoma of the urogenital tract. Int Urol Nephrol 2009;41:13–7. 61. Bacci G, Longhi A, Briccoli A, et al. The role of surgical margins in treatment of Ewing’s sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2006;65:766–72. 62. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al. Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 2005;104: 367–73. 63. La TH, Meyers PA, Wexler LH, et al. Radiation therapy for Ewing’s sarcoma: results from memorial Sloan-Kettering in the modern era. Int J Radiat Oncol Biol Phys 2006;64:544–50. 64. Wexler LH, DeLaney TF, Tsokos M, et al. Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing’s sarcoma family of tumors. Cancer 1996;78:901–11.
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Review
Intraspinal Ewing’s sarcoma/primitive neuroectodermal tumors Yong Yan , Tao Xu , Juxiang Chen ⇑, Guohan Hu, Yicheng Lu Department of Neurosurgery, Changzheng Hospital, Neurosurgery Research Institution of Shanghai, 415 Fengyang Street, Huangpu District, Shanghai 200003, China
a r t i c l e
i n f o
Article history: Received 13 August 2010 Accepted 22 September 2010
Keywords: Ewing’s sarcoma Intradural–extramedullary spinal cord neoplasms Intramedullary spinal cord neoplasms Malignant spinal cord neoplasms Primitive neuroectodermal tumors
a b s t r a c t Intraspinal Ewing’s sarcoma (ES) and primitive neuroectodermal tumors (PNET) are very rare, and the characteristics and prognoses of the disease remain unclear. We present an illustrative patient with an intradural, extramedullary PNET arising within the cervical spinal canal, with clinical and radiological manifestations of leptomeningeal spread, and review the reports of a further 77 patients with intraspinal ES/PNET. Cox regression analyses showed that tumor location (extradural, intradural) (p = 0.002, RR = 4.217, 95% confidence interval [CI] 1.668–10.664) and spinal segment location (cervical, thoracic, lumbar, or sacral) (p = 0.017, RR = 2.040, 95% CI 1.133–3.673) were independent factors in the prognosis of intraspinal ES/PNET. We concluded that a peripheral PNET may originate within the spinal canal and exhibit leptomeningeal spread similar to that seen in central PNET, and that a patient with an intradural ES/PNET high in the spinal canal is more likely to have a poor prognosis. Ó 2010 Published by Elsevier Ltd.
1. Introduction Ewing’s sarcoma (ES) and primitive neuroectodermal tumors (PNET) have been defined as two separate diseases occurring at different sites with different origins. ES was thought to be a malignant tumor originating from marrow mesenchymal stem cells and was predisposed to growing in the extremities, whereas PNET signified all embryonal tumors of the central nervous system (CNS), regardless of their sites of origin.1,2 ES and PNET had similar histologic appearances, consisting of monomorphic, undifferentiated, small, round, hyperchromatic cells. With the finding that ES also occurred in soft tissue (extraskeletal ES), and that tumors outside the CNS were derived from the neural crest (peripheral PNET), the definitions of ES and PNET began to overlap.3 Accordingly, PNET derived in the CNS was named central PNET (cPNET) to differentiate it from peripheral PNET (pPNET).4 Cytogenetic analysis detected the presence of a reciprocal translocation t(11;22)(q24;q12) or t(21;22)(q22;q12) with high frequency (up to 95%) in both pPNET and ES, whereas this translocation was not detected in cPNET.4,5 Fusion genes led to the abnormal expression of a series of polypeptides or proteins, with the most common being CD99. Immunoreactivity to CD99 was present in extraskeletal ES and peripheral PNET, but absent in central PNET. Therefore, ES and pPNET represented two ends of the spectrum of the same tumoral entity, with diverse degrees of histological differentiation. pPNET displayed many properties
⇑ Corresponding author. Tel.: +86 21 81885673.
E-mail address: [email protected] (J. Chen). The first two authors contributed equally to the article.
0967-5868/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.jocn.2010.09.012
of neurogenic tumors, including positive immunoreactivity for neuronal markers (neuron-specific enolase [NSE] and synaptophysin [syn]), light microscopic evidence of Homer-Wright rosettes, and ultrastructural evidence of neuronal differentiation (interdigitating cell processes and neurosecretory granules).6,7 ES did not display such differentiated properties. Therefore, ES was considered to be the least differentiated, and pPNET was the most differentiated member of the ES family.8 Intraspinal ES/PNET is rare, and the characteristics and prognosis of the disease remain unclear. Our literature search revealed reports of 78 patients with ES/PNET located within the spinal canal,3,4,9–58 and we discuss the clinical characteristics, factors affecting prognosis, and treatment choices of the disease. In addition, we present an illustrative patient with an intradural, extramedullary pPNET arising within the cervical spinal canal that was associated with a rapidly deteriorating clinical course and poor prognosis.
2. Illustrative patient A 10-year-old Chinese boy presented with a 20-day history of neck pain and worsening muscle weakness, as well as a 1-week history of dysuria. Neurological examination revealed bilateral hypoesthesia in the upper limbs and paralysis of the extremities, with 2/5 strength in the right arm, 3/5 strength in the right leg, and 4/5 strength in the left limbs. The patient was also found to have flaccid muscle tone and reduced tendon reflexes in the right arm. The patient’s MRI scan revealed an extramedullary mass to the right of C2–C3, causing severe compression of the spinal cord. The
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mass measured 3.0 cm by 2.0 cm by 1.5 cm and had long T1weighted and T2-weighted signals on MRI, with homogeneous and intermediate post-contrast enhancement. An unusual feature was pial enhancement, extending above the tumor (Fig. 1). There was no clinical or radiologic evidence of cerebellar medulloblastoma or other intracranial tumors. A laminectomy was performed to decompress the spinal cord and debulk the tumor. A grey-reddish colored, well-circumscribed lesion with moderate blood supply and intact pseudocapsule was found on the opening of the spinal dura (Supplementary Fig. 1). The lesion was closely related to the cervical nerves, with no extension to the dura matter or spinal cord. The tumor was totally removed via bolck resection. Muscle strength in the extremities improved to 5/5 after surgery. The boy had urinary difficulty on the first few days after surgery, but soon recovered to normal. Unfortunately, the child’s condition deteriorated. He developed dizziness and nausea, hearing loss, facial paralysis, oculomotor nerve paralysis, seizures, and limb movement disturbance. Seeding metastasis of the tumor into the cerebrospinal fluid (CSF) was suspected; however, no tumor cells were detected on CSF cytological analysis. There were, however, many lymphocytes. The child was transferred to another hospital to receive radiation treatment; however, he died just before the radiation could be given. It was approximately 30 days after surgery. The tumor had a tough texture and a gray-white cut-surface macroscopically. Microscopically, the tumor was composed of diffuse solid sheets of small cells with scanty cytoplasm, round–oval nuclei, inconspicuous nucleoli, and fine chromatin. Rosettes were present (Supplementary Fig. 2a). The tumor cells were strongly positive for CD99 (Supplementary Fig. 2b), weakly positive for vimentin, and negative for syn, cytokinin, desmin, glial fibrillary acidic protein, leucocyte common antigen, neurofilament protein, NSE, S-100, actin, myogenic differentiation antigen 1, chromogranin A, myeloperoxidase, terminal deoxynucleotidyl transferase, and lymphoid markers (including CD19, CD5, CD10, CD20, CD2, CD117, CD79a, CD3, and CD34). The immunohistochemical characteristics were consistent with pPNET. 3. Review of the literature We found a total of 78 patients with intraspinal PNET (55) and ES (23) in the literature (Table 1). Survival time, and variables
including age (615, 16–30, 31–60, P61 years), sex (male, female), resection extent (biopsy, partial resection, subtotal or total resection), spinal level (lumbar and sacral, thoracic, cervical), tumor location (extradural, intradural), radiotherapy (yes, no), chemotherapy (yes, no), and pathology (PNET, ES) were collected to perform Cox regression analysis on the prognostic factors of these 78 patients with intraspinal ES/PNET. Calculations were done using the Statistical Package for the Social Sciences version 17.0 (SPSS, Chicago, IL, USA). 3.1. Cox regression analysis of prognostic factors From the available data (Table 1), we found that ES/PNET is more likely to occur in males (male/female = 1.8849/26) and young people (age < 25 years/P25 years = 2.052/26). It was more likely to occur in the lower spinal canal than in the upper (cervical [n = 19, 24.7%], thoracic [n = 25, 32.5%], lumbar and sacral [n = 33, 42.9%]). Most tumors (n = 70, 89.7%) occurred in the extradural space (extradural [n = 31, 44.3%], cauda equina [n = 13, 18.6%], extramedullary [n = 12, 17.1%], intra–extramedullary [n = 5, 7.1%], and intramedullary [n = 9, 2.9%]). ES was more common extradurally (n = 17, 85.0%), and PNET was more common intradurally (n = 37, 74.5%). Cervical extramedullary PNET was rare: to our knowledge, only four patients have been reported. Leptomeningeal spread of the tumor was common in cPNET, but rare in pPNET. To our knowledge, ours is the first report of pPNET with leptomeningeal spread. Cox regression analysis showed that tumor location (p = 0.002, RR = 4.217, 95% confidence interval [CI] 1.668–10.664) and spinal cord level (p = 0.017, RR = 2.040, 95% CI 1.133–3.673) were independent factors in the prognosis of spinal ES/PNET patients. Thus, patients with intradural and high spinal cord level ES/PNET have a poor prognosis. 3.2. Clinical features Given the clinical differences seen in cPNET and pPNET, it is necessary to separate the two. Although both cPNET and pPNET are aggressive tumors, pPNET is known to be metastatic and invasive, while cPNET rarely metastasizes outside the CNS.4 An interesting finding in our patient is the unusual pial enhancement. On close examination, the pial enhancement extended inferiorly to the cervical–thoracic junction and posteriorly and superiorly to the ventral medulla and pons (Fig. 1), which suggests that a pPNET
Fig. 1. Post-contrast MRI of a 10-year-old Chinese boy: (a) sagittal T1-weighted MRI showing a moderately enhanced lesion in the intradural and extramedullary space at the C2–C3 level; and (b) coronal T1-weighted MRI showing unusual pial enhancement extending superiorly, involving the ventral medulla and pons, and extending inferiorly as far as the cervicothoracic junction, particularly posteriorly.
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Y. Yan et al. / Journal of Clinical Neuroscience 18 (2011) 601–606 Table 1 Reports of patients with spinal Ewing’s sarcoma (ES)/primitive neuroectodermal tumors (PNET). Yearref 9
1969 197810 197810 197810 198511 198511 198511 198712 198713 198814 198814 198915 199116 199217 199217 199217 199217 199217 199217 199217 199218 199319 199319 199420 199421 199622 199623 199623 199724 199725 199826 199827 199928 199928 199929 199930 200031 200032 200133 200134 200134 200134 200134 200134 200135 200236 200237 200238 200339 200339 20032 20032 20032 20032 200440 200441 200442 200443 200544 200645 20064 200646 200647 200648 200749 200749 200749 200750 200750 200751 200852 200853 200854 200855
Age/sex
Level
Location
Treatment
Survival (m)
Diagnosis
24 y/M <10 y/N.A. <10 y/N.A. <10 y/N.A. 24 y/M 56 y/M 39 y/M 26 y/F 26 y/M 26 y/M 15 y/F 7 y/M 7 y/M 21 y/F 13 y/F 23 y/M 24 y/M 16 y/M 12 y/M 22 y/F 16 y/F 17 y/M 11 m/M 47 y/M 41 y/M 3 m/F 7 y/F 14 y/M 14 y/F 14 y/M 23 y/F 2 y/F 32 y/M 17 y/M 16 y/M 7 y/F 52 y/M 12 y/F 13 y/F 29 y/F 18 y/M 22 y/M 31 y/M 13 y/M 21 y/M 69 y/M 5 y/M 18 y/F 49 y/F 29 y/F 12 y/F 10 y/M 30 y/F 14 y/M 17 y/M 31 y/M 16 y/M 26 y/M 37 y/M 70 y/M 2 y/M 38 y/M 54 y/F 28 y/F 8 y/M 9 y/M 18 y/M 27 y/M 16 y/F 19 y/F 4 y/F 27 y/M 13 y/F 12 y/M
L C C TL L4–5 L2–3 L L4–Sa1 C2–3 T1–5, L3–4 T8–L2 T4–Sa3 L1–2 C4–5 T10 T10 L1 L3 L3 L5–Sa1 L2 L4–Sa1 C5–T1 L3–Sa1 T T7–L5 L5–Sa1 L4–5 T12–L1 T12–L1 T9–10 C1–C6 Sa1 L3–5 N.A. L5–Sa1 L2–5 C7–T4 C7–T11 C3–5 T8 L5–Sa1 L3–4 C3–5 T10–11, L1–2 C7–T3 C7–T1 L3–5 L2 T2, T10–11 T1–3 C6–T3 C2–4 L1–2 T11–L2 LS T8–9 L1 L L4–Sa1 C2–6 T1–3 C2–5 L C2–4 T9–L1 C–T L4–5 L2–Sa1 T11–L2 T11–L3/4 Sa1–2 L T7–9
CE N.A. N.A. N.A. CE CE CE Extradural Extramedullary Intra–extramedullary Intra–extramedullary Intramedullary Extradural Extradural Extradural Extradural Extradural Extradural Extradural Extradural Intramedullary Extradural N.A. CE Extramedullary Intramedullary N.A. N.A. Intramedullary CE Extramedullary Intra–extramedullary Extradural Extradural N.A. CE CE Extradural Extradural Extradural Extradural Extradural Extradural Extradural Intra–extramedullary Intra–extramedullary Extradural Extramedullary CE Intramedullary Extradural Extradural Extramedullary Extramedullary Intramedullary CE Extradural Extradural Extramedullary CE Intramedullary Intramedullary Intramedullary Extradural Extradural Extramedullary Intramedullary Extradural CE Extramedullary Extradural CE Extradural Extradural
S, RT S, RT, CT N.A. N.A. S (TR), RT S, RT S, RT S, RT S(TR), RT S, RT S, RT, CT Biopsy, CT, RT S(PR), CT S(TR), CT Biopsy, RT, CT S(TR), RT, CT S(TR), RT, CT S(subTR), RT, CT S(subTR), RT, CT S(PR), RT, CT N.A. S(PR), RT, CT S(subTR), RT, CT Biopsy, RT, CT N.A. Biopsy, RT, CT RT, S(subTR), CT S(subTR), CT S(TR), CT, RT N.A. S(subTR), RT, CT S, RT S(TR), RT, CT S(TR), CT, RT N.A. S(PR), CT, RT S(PR), RT Biopsy, RT Biopsy, CT, RT S(PR), CT, RT S(PR), CT, RT Biopsy, CT, RT S(PR), CT, RT S(PR), CT, RT S(TR), RT, CT S(PR), RT S(TR), RT S(PR), CT, RT S(TR), RT, CT Biopsy, RT, CT S(PR), CT, RT S(PR), CT, RT S(PR), CT, RT S(TR), CT, ASCR S(STR), RT S, RT, CT S(TR), RT, CT S(TR), CT, RT S(PR), RT S(PR), RT, CT Biopsy Biopsy, CT S(PR), RT S, RT, CT S(TR) S(subTR), RT, CT Biopsy, RT, CT S(TR), CT, RT S(PR), CT, RT S(TR), RT, CT, ASCR S(subTR), RT, CT S(TR), RT, CT N.A. S(TR), CT, RT
10 <24 <24 <24 18 Alive at 36 42 Alive at 6 10 d 36 18 20 Alive at 40 Alive at 6 Alive at 10 y 7 10 >2 6.5 y <14 29 Alive at 7 y Alive at 2 y 16 Alive at 36 0.5 Alive, in remission 8 Alive at 15 Alive at 3 Alive at 12 Several d 29 Alive at 23 N.A. 18 Alive at 12 Alive at 4 Alive at 31 Alive at 30 Alive at 18 Alive at 15 Alive at 32 Alive at 11 Alive at 30 3 Alive at 8 Alive at 25 23 17 32 22 14 Alive at 67 Alive at 4 2 Alive at 7 Alive at 17 6 Alive at 12 7d 18 N.A. Alive at 24 Recurrent at 8 Alive at 18 Alive at 6 Alive at 72 Alive at 5 Alive at 24 Alive at 22 Alive at 24 N.A. Alive at 20
PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET PNET ES ES ES ES ES ES ES ES PNET ES ES PNET PNET PNET ES ES PNET PNET PNET PNET pPNET pPNET PNET ES pPNET Infected ES pPNET ES ES ES ES ES ES PNET PNET PNET pPNET PNET ES PNET PNET PNET pPNET pPNET PNET PNET PNET pPNET cPNET PNET cPNET pPNET PNET PNET PNET pPNET pPNET pPNET ES PNET PNET ES
(continued on next page)
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Table 1 (continued) Yearref
Age/sex
Level
Location
Treatment
Survival (m)
Diagnosis
200856 200957 201058 Illustrative patient
24 y/M 29 y/M 45 y/M 10 y/M
T, TL T9–10 C3–5 C2–3
Extradural Extramedullary Extramedullary Extramedullary
S, RT S(PR), CT S(subTR) S(TR)
Alive at 12 4 13 1
pPNET pPNET pPNET pPNET
ASCR = Autologous stem cell rescue, C = cervical, CE = Cauda equina, C–T = cervicothoracic, CT = chemotherapy, d = days, F = female, L = lumbar, LS = lumbosacral, m = month, M = male, N.A. = not available, PR = partial resection, RT = radiotherapy, Sa = Sacral, subTR = subtotal resection, S = surgery, T = thoracic, TL = thoracolumbar, TR = total resection, y = year.
Fig. 2. Postoperative MRI at (a, c, e) 10 days, and (b, d, f) 20 days after surgery showing pathologic changes of the posterior fossa contents: (a, b), sagittal post-contrast T1weighted MRI showing swelling of the posterior fossa contents and narrowing of the cerebrospinal fluid effluent passage – the pia matter enhancement was more extensive and obvious in (b); (c, d) axial post-contrast T1-weighted MRI showing swelling of the vestibulocochlear and facial nerves signified by the increase in abnormal signals in the cerebellopontine angles; and (e, f) axial T2-weighted MRI showing increased subpial edema of the cerebellar cortex (f), leading to swelling of the cerebellum.
may originate within the spinal canal and exhibit leptomeningeal spread similar to that seen in cPNET. Most spinal ES/PNET lesions demonstrate the following clinical characteristics: a space occupying lesion with neural compression as the main clinical symptom; long T1-weighted and T2-weighted signals on MRI, with some enhancement of the solid component of
the tumor post-contrast. The mass is usually well circumscribed, is generated from the meninges and cauda equina, infiltrates the neural foramen, and encases spinal nerves and vascular structures:4,45,47,58,59 all of which were found in the illustrative patient. Our patient temporarily improved during the first week after surgery, but shortly thereafter, he developed dizziness, nausea, and
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symptoms involving cranial nerves III, VII, and VIII. Subsequent MRI scans revealed subpial edema on the surface of the cerebral peduncle, pons, medulla oblongata, and cerebellum, indicating leptomeningeal spread of the tumor cells to these sites (Fig. 2a, b, e, f). Cranial nerves in the cerebellopontine angle swelled, which could explain the hearing loss and facial paralysis (Fig. 2b, c). Increasing edema caused the posterior contents to swell and obstruct the CSF effluent passages (Fig. 2a, b, e, f). Despite insertion of a shunt to release the obstructive hydrocephalus, the child died within a few days before any adjunctive therapy could be given. All the symptoms mentioned above are closely related to the leptomeningeal spread of the tumor cells, which is very rare in pPNET. 3.3. Treatment options The treatment for ES/PNET includes surgical resection, irradiation, and chemotherapy.60 The significance of surgical resection lies first in the confirmation of the diagnosis. Lacking clinical and radiographic specificity, it is often difficult to differentiate ES/PNET from other diseases in the spinal canal, including schwannoma, meningioma and glioma; therefore, a pathological examination after surgery is essential for diagnosis. Second, reducing the tumor volume by surgical resection is the basis for other adjuvant treatments, including radiotherapy and chemotherapy. It has been reported that post-operative irradiation has a better effect than irradiation alone.61,62 Radiotherapy includes local irradiation and neuroaxis irradiation, and the choice between the two methods depends on the general condition of the patient and the nature of the disease. Chemotherapy is another choice. The combination of ifosfamide and etoposide, in conjunction with vincristine, doxorubicin and cyclophosphamide based therapy, has significantly improved response rates and survival in patients with ES/PNET.59,62–64 However, in intrathecal ES/PNET, the blood–brain barrier prevents chemotherapeutic agents from gaining access to the tumor. Categories of agents suitable for intrathecal injection are very limited, and most of these agents are not suitable for the tumor. Therefore, intrathecal ES/PNET is difficult to treat. In our patient, the rapid progression of the disease precluded further treatment. The poor prognosis is partly related to the nature of the disease, and partly to our unfamiliarity with it. A more detailed understanding of intraspinal ES/PNET may allow better treatment options for this rare disease. Acknowledgements This study was supported by a grant from China 863 Project (2007AA02Z483) and the National Natural Science Foundation (30772247). We also thank Dr Xiaojun Wu and Dr Tao Wang for their clinical work. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2010.09.012. References 1. Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer 1973;32:890–7. 2. Rorke LB. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983;42:1–15. 3. Harimaya K, Oda Y, Matsuda S, et al. Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 2003;28:E408–12. 4. Kampman WA, Kros JM, De Jong TH, et al. Primitive neuroectodermal tumours (PNETs) located in the spinal canal; the relevance of classification as central or peripheral PNET: case report of a primary spinal PNET occurrence with a critical literature review. J Neurooncol 2006;77:65–72.
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