Primary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature

Clinical Neurology and Neurosurgery 104 (2002) 36 – 40 www.elsevier.com/locate/clineuro

Primary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature Christian Mawrin a,c,*, Hans J. Synowitz b, Elmar Kirches a, Evelyn Kutz d, Knut Dietzmann a, Serge Weis a a

Department of Neuropathology, Otto-6on-Guericke-Uni6ersity, Leipziger Strasse 44, D-39120 Magdeburg, Germany Department of Neurosurgery, Otto-6on-Guericke-Uni6ersity, Leipziger Strasse 44, D-39120 Magdeburg, Germany c Department of Psychiatry, Otto-6on-Guericke-Uni6ersity, Leipziger Strasse 44, D-39120 Magdeburg, Germany d Department of Radiooncology, Johanniter Hospital, Stendal, Germany

b

Received 13 August 2001; accepted 3 October 2001

Abstract We present the clinical, radiological, and pathological features of a primary primitive neuroectodermal tumor (PNET) that occurred in the thoracic spinal cord of a 69-year-old man. Magnetic resonance imaging (MRI) demonstrated on T1-weighted images a 2 ×1× 5 cm isointense intraspinal mass with homogeneous contrast enhancement extending from the C7 to the Th3 level. There was no clinical or radiological evidence for the existence of an intracranial tumor. Histological examination revealed a small round cell tumor with rosette formation and immunohistochemical characteristics of a PNET. The patient is the oldest among the 20 cases with this rare spinal cord neoplasm reported so far in the literature; the previously published cases are briefly reviewed. © 2002 Elsevier Science B.V. All rights reserved. Keywords: PNET; Spinal cord; MRI

1. Introduction Primitive neuroectodermal tumors (PNETs), a term proposed in 1973 by Hart and Earle [1], are a group of malignant neoplasms which arise from pluripotent neural crest cells. These tumors are usually composed of undifferentiated, small, round, hyperchromatic cells. They occur predominantly in childhood and young adults [2]. PNETs may originate in the central nervous system (CNS) or peripherally in the adrenal gland and sympathetic ganglia [2]. In the CNS, these tumors most frequently arise in the cerebellum of children. At this site they have traditionally been called medulloblastomas [3,4]. Compared with the high frequency of medulloblastomas among primary brain tumors, primary intraspinal PNETs are exceptionally rare. To date, only * Corresponding author. Tel.: + 49-391-671-5814; fax: + 49-391671-3300. E-mail address: [email protected] (C. Mawrin).

20 cases of primary intraspinal PNETs have been reported in the literature. Among these cases, the cauda equina seems to be a preferred site of manifestation [5–10]. In this report, we describe a patient with a primary PNET of the thoracic spinal cord, who represents the oldest among the cases reported so far in the literature.

2. Patient profile This 69-year-old man was admitted to the hospital with a 5-month history of gait disturbances and a progressive weakness of the left leg. The remaining medical history was unremarkable with the exception of traumatic upper left arm amputation during the adolescence; longstanding idiopathic arterial hypertension was treated with a beta blocker and acetylsalicylic acid. His familial medical history was unremarkable. Physical and neurological examination on admission revealed a hypesthesia on the left side from the Th5 level down to

0303-8467/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 1 ) 0 0 1 7 1 - 8

C. Mawrin et al. / Clinical Neurology and Neurosurgery 104 (2002) 36–40

the feet. Furthermore, a distinct paresis of dorsiflexion on the left leg, and a patellar and feet clonus on this side were evident. His knee and ankle reflexes were bilaterally brisk. Otherwise clinical examination was unremarkable. The preoperative routine blood count, clotting profiles, electrolytes and blood chemistry were all within the normal limits. Magnetic resonance imaging (MRI) of the spinal cord demonstrated on T1weighted images a 2×1 × 5 cm isointense intraspinal mass with homogeneous signal enhancement after addition of gadolinium–diethylenetriamine pentaacetic acid (Gd –DTPA) that extended from C7-Th3 (Fig. 1). The radiological growth pattern of the tumor was highly suggestive of an ependymoma. MRI with gadolinium enhancement of the brain was unremarkable. Additionally, metastasis from a pulmonary neoplasm could be excluded on chest survey X-ray photograph. A left-sided hemilaminectomy at the Th1– Th2 level revealed a grey–reddish soft tumor with prominent vascularisation. The intra- and extramedullary located tumor was poorly demarcated. A diagnosis of small round cell neoplasm was made on frozen section. The tumor was considered non-resectable, and therefore only partly removed to establish the final histological diagnosis. Following surgery, the patient improved

37

gradually. After his surgical wound had healed, he received spinal cord irradiation from C6 to Th3 with a total dose of 50.4 Gy. The irradiation was well tolerated, and despite the disability due to the traumatic amputation of the left arm and a remaining incomplete paralysis of the left leg, he was able to walk with a crutch 8 weeks after operation. Postoperative MRI scan of the spinal cord was not performed. Four weeks after discharge from the hospital, after he had fallen down at home the patient experienced progressive weakness of the left leg. A fracture could be excluded by X-ray photograph. After readmission to an outside hospital, he developed severe pneumonia, and finally he died 12 weeks after the diagnosis of the spinal PNET. Autopsy was refused.

3. Methods Tumor samples for histological and immunohistochemical examinations were fixed in 4% buffered formaldehyde and embedded in paraffin. Paraffin sections were stained with hematoxylin and eosin (HE) and luxol fast blue. Immunohistochemical staining using the biotin-streptavidin peroxidase technique (LSAB2 kit,

Fig. 1. Sagittal MRI scans demonstrate a diffuse intraspinal tumor extending from C7 to Th3. The tumor is isointense on T1-weighted images (A, arrow; inset shows enlarged view of the tumor) and hyperintense on T2-weighted images (C). After the administration of Gd – DTPA, the tumor shows a marked homogeneous signal enhancement (B).

38

C. Mawrin et al. / Clinical Neurology and Neurosurgery 104 (2002) 36–40

Fig. 2. (A) Photomicrograph of the primitive neuroectodermal tumor showing a poorly differentiated cellular tumor composed of small round cells with high nuclear to cytoplasmic ratio and rosette formation. H&E, × 400. (B) Synaptophysin immunoreactivity appears as dense surface granular staining (arrows), or finely dotted staining in some tumor cells. Synaptophysin immunostaining, ×400.

DAKO) was performed with the following antibodies: neuron specific enolase (NSE) (monoclonal, DAKO; 1:2000), neurofilament (NF) protein (monoclonal, clone 2F11 (DAKO); 1:100), glial fibrillary acidic protein (GFAP) (polyclonal, Sigma; 1:1500), synaptophysin (monoclonal, clone SY38 (DAKO); 1:200), cytokeratin (monoclonal, clone MNF116 (DAKO); 1:50), vimentin (monoclonal, clone Vim3B4 (DAKO); 1:200), S-100 protein (polyclonal, DAKO; 1:5000), and leucocyte common antigen (LCA) (monoclonal, clone 2B11 (DAKO); 1:1000). In order to evaluate the proliferative activity of the tumor cells, MIB-1 immunostaining with anti-human Ki-67 antibody (monoclonal, clone Ki-S5 (DAKO); 1:50) was also performed. To enhance the immunoreactivity, the sections were pretreated in a microwave oven, adjusted to 780 W, for 20 min.

4. Results Macroscopically, the small tumor sample was soft and of red-beige colour. On conventional light microscopic examination the tumor tissue was found to be composed of closely packed uniform small round cells with scant cytoplasm and hyperchromatic nuclei. The undifferentiated round cells occasionally formed true Homer –Wright rosettes, and infrequently a perivascular arrangement of the tumor cells was noted (Fig. 2A). Mitotic figures, as well as necrotic areas and hemorrhages, were frequently seen. Immunohistochemical studies demonstrated a positive reaction for synaptophysin (Fig. 2B), NSE, and S-100 protein. Additionally, focal staining of residential glial cells for GFAP, as well as small tumor areas immunoreactive for vimentin were noted. Immunohistochemical reactions against cytokeratin, LCA, and NF were all negative. The mean per-

centage of MIB-1 positive tumor cells was 26%. Both histological and immunohistochemical features of this round-cell tumor were consistent with the diagnosis of PNET.

5. Discussion Primary intraspinal PNET is very rare, and to our knowledge only 20 cases have been reported so far in the literature, which are summarized together with the present case in Table 1. Although intraspinal PNETs can arise at any level of the spinal cord, there seems to be a predilection for the cauda equina (Table 1). This might be due to the fact that the cauda equina forms already part of the peripheral nervous system, where the axons have become dependent on Schwann cells for the maintenance of their myelin sheaths [8]. However, keeping in mind that PNETs are thought to arise from neoplastic transformation of primitive neuroepithelial cells in subependymal zones [11], there is no explanation for the difference in the incidence of PNETs in different locations of the CNS, as the subependymal zone can persist in any part of the CNS. The age of manifestation, including our own case, ranged from 7 to 69 years with an average age of 28 years. Because this is much older than the average age of manifestation of intracranial PNETs, spinal PNETs appear to be more common in adults than in children. Among the intraspinal PNETs, our patient represents the oldest one of the cases published so far. In addition, there seems to be a male predominance for this tumor (Table 1). Since the initial definition by Hart and Earle in 1973 of PNET as tumors containing 90 to 95% undifferenti-

C. Mawrin et al. / Clinical Neurology and Neurosurgery 104 (2002) 36–40

ated cells [1], the classification of this embryonal tumour has been controversial. In 1983, Rorke [11] and Becker and Hinton [3] independently proposed classifying all CNS tumors with a predominant undifferentiated, primitive cell component as PNETs. To circumvent these controversies, the recent World Health Organization classification of brain tumors recommended to use PNET as a generic term for cerebellar medulloblastomas and other CNS tumors that are morphologically identical to medulloblastomas [4]. Histologically, PNETs are undifferentiated small, round-cell tumors with hyperchromatic nuclei and features of neural differentiation, which typically form either Homer– Wright or Flexner– Winterstein rosettes [2]. The amount and quality of rosette formation can vary substantially, and some tumors may only show abortive rosette formation [5]. Recently, one case of a spinal PNET with distinct ganglioneuroma-like areas has been reported [5]. Usually by means of immunohistochemical characteristics, PNETs must be distinguished from other morphologically similar tumors such as lymphoma, rhabdomyosarcoma, small-cell carcinoma, and Ewing’s sarcoma [5]. The latter shares several interesting features with PNETs, for instance

39

the same reciprocal chromosomal translocation t(11;22) (q24:q12), or expression of the glycoprotein CD99 [5,12,13]. Differential diagnostic considerations regarding the intraspinal localisation, such as meningioma, schwannoma, neurofibroma, and ependymoma, are easily made on routine histologic examination. Before the diagnosis of primary spinal PNET can be confirmed, the more common ‘drop’ metastases of intracranial origin must be excluded. Interestingly, the dissemination of a primary spinal PNET in an ascending manner into the intracranial space along the cerebrospinal fluid (CSF) pathway have been repeatedly observed [7,8,14]. In contrast, these tumors do rarely metastasize outside the neuraxis (Table 1). In our patient, MRI examination of the head disclosed tumor manifestation. The major radiological differential diagnosis for intraspinal PNETs are ependymomas, which are the most common intramedullary tumors. On MR imaging, spinal ependymomas are isointense on T1-weighted images, with strong signal enhancement after contrast medium application [15]. Because these radiological features were also observed in our patient, the differentiation between the benign ependymoma and an in-

Table 1 Summary of 21 cases with primary intraspinal primitive neuroectodermal tumors Patient

Sex

Age (year)

Level

Location

Metastases

Survival (mo)

Reference

1 2 3 4

M NA NA NA

24 NA NA NA

Lumbar Cervical Cervical Thoracolumbar

Cauda equina Unknown Unknown Unknown

10 B24a B24a B24a

Smith et al. [10] Kosnick et al. [18]

5 6 7 8

M M M M

24 56 39 26

Lumbar Lumbar Lumbar Cervical

18 Alive at 36 42 36

Kepes et al. [8]

9 10

F F

26 15

Alive at 6 18

Liu et al. [20] Jaksche et al. [7]

11 12 13

M M F

26 7 16

Cauda equina Cauda equina Cauda equina Intradural extramedullary Lumbosacral Extradural Thoracolumbar Intra-and extramedullary Lumbar/Thoracic Cauda equina Thoracolumbar Intramedullary Lumbar Intramedullary

Lung None None Lung, bone, lymph node Leptomeningeal None None Pleura, bone, lymph nodes None None Brain None Brain

36 20 29

14 15 16 17

M M F F

47 14 14 23

Lumbar Lumbar Thoracolumbar Thoracic

None None None None

16 Alive at 3 Alive at 15 Alive at 12

18

M

32

Sacral

Cauda equina Cauda equina Intramedullary Intradural extramedullary Intradural

Leptomeningeal

29

19 20 21

M M M

17 52 69

Lumbar Lumbar Thoracic

Epidural Cauda equina Intra- and extramedullary

None None None

23 Alive at 12 3

a

Sevick et al. [19]

Freyer et al. [21] Ogasawara et al. [14] McDermott et al. [9] Hisaoka et al. [5] Deme et al. [16] Papadatos et al. [22] Dorfmuller et al. [17] Isotalo et al. [6] Present case

The authors described 15 cases with cerebral and three cases with spinal PNET. Among these, all the 12 cases with adequate follow-up information survived for less than 24 months, but it is not clear from the article whether the spinal cases were included in the 12. M, male, F, female, NA, not available.

40

C. Mawrin et al. / Clinical Neurology and Neurosurgery 104 (2002) 36–40

traspinal PNET might be difficult; investigations of larger series may help to unravel more distinct radiological characteristics of intraspinal PNETs. The treatment of intraspinal PNETs comprises in the first line operative decompression to resolve the sometimes acute progressive neurologic deficit [16], followed by high-dose irradiation of the tumor region or the entire neuraxis, and by a multi-agent chemotherapy [17]. Despite this treatment, the prognosis of intraspinal PNETs is poor; more than 57% of the patients died within 36 months (Table 1). In our patient, despite radiation therapy, the neurological function worsened rapidly after discharge from the hospital, probably indicating rapid tumor growth. However, due to the lack of radiological reevaluation and postmortem examination the exact extension of the remaining tumor could not be determined. Although survival time was very short in our patient compared to other cases from the literature, with regard to the pneumonia the significance of the spinal PNET as the cause of death remains unclear.

References [1] Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer 1973;32(4):890 – 7. [2] Dehner LP. Peripheral and central primitive neuroectodermal tumors. A nosologic concept seeking a consensus. Arch Pathol Lab Med 1986;110(11):997 –1005. [3] Becker LE, Hinton D. Primitive neuroectodermal tumors of the central nervous system. Hum Pathol 1983;14(6):538 –50. [4] Embryonal tumours. In: Kleihues P, Cavenee WK, editors. Tumors of the Nervous System. Lyon: IARC Press, 2000. pp. 123 – 144. [5] Hisaoka M, Hashimoto H, Murao T. Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina. Virchows Arch 1997;431(5):365 – 9. [6] Isotalo PA, Agbi C, Davidson B, Girard A, Verma S, Robertson SJ. Primary primitive neuroectodermal tumor of the cauda equina. Hum Pathol 2000;31(8):999 –1001. [7] Jaksche H, Wockel W, Wernert N. Primary spinal medulloblastomas? Neurosurg Rev 1988;11(3 –4):259–65.

[8] Kepes JJ, Belton K, Roessmann U, Ketcherside WJ. Primitive neuroectodermal tumors of the cauda equina in adults with no detectable primary intracranial neoplasm — three case studies. Clin Neuropathol 1985;4(1):1 – 11. [9] McDermott VG, el Jabbour JN, Sellar RJ, Bell J. Primitive neuroectodermal tumour of the cauda equina. Neuroradiology 1994;36(3):228 – 30. [10] Smith DR, Hardman JM, Earle KM. Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 1969;31(1):50 – 8. [11] Rorke LB. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983;42(1):1 – 15. [12] Dehner LP. Primitive neuroectodermal tumor and Ewing’s sarcoma. Am J Surg Pathol 1993;17(1):1 – 13. [13] Brinkhuis M, Wijnaendts LCD, van der Linden JC. Peripheral primitive neuroectodermal tumour and extra-osseous Ewing’s sarcoma: a histological, immunohistochemical and DNA flow cytometry study. Virchows Arch 1995;425:611 – 6. [14] Ogasawara H, Kiya K, Kuriso K, Muttaqin Z, Uozumi T, Sugiyama K, Kawamoto Y, Iida K. Intracranial metastasis from a spinal cord primitive neuroectodermal tumor: case report. Surg Neurol 1992;37:307 – 12. [15] Cysts, tumors, and tumorlike lesions of the spine and spinal cord. In: Osborn AG, editor. Diagnostic Neuroradiology. St. Louis: Mosby, 1994. pp. 876 – 918. [16] Deme S, Ang LC, Skaf G, Rowed DW. Primary intramedullary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature. Neurosurgery 1997;41(6):1417 –20. [17] Dorfmuller G, Wurtz FG, Umschaden HW, Kleinert R, Ambros PF. Intraspinal primitive neuroectodermal tumour: report of two cases and review of the literature. Acta Neurochir (Wien) 1999;141(11):1169 – 75. [18] Kosnick EJ, Boesel CP, Bay J, Sayers MP. Primitive neuroectodermal tumors of the central nervous system in children. J Neurosurg 1978;48:741 – 6. [19] Sevick RJ, Johns RD, Curry BJ. Primary spinal neuroectodermal tumor with extraneural metastases. AJNR Am J Neuroradiol 1987;8:1151 – 2. [20] Liu HM, Yang WC, Garcia RL, Noh JM, Malhotra V, Leeds NE. Intraspinal primitive neuroectodermal tumor arising from the sacral nerve root. J Comput Tomogr 1987;11:350 –4. [21] Freyer DR, Hutchinson RJ, McKeever PE. Primary primitive neuroectodermal tumor of the spinal cord associated with neural tube defect. Pediatr Neurosci 1989;15:181 – 7. [22] Papadatos D, Albrecht S, Mohr G. Carpio-O’Donovan Rd. Exophytic primitive neuroectodermal tumor of the spinal cord. AJNR Am J Neuroradiol 1998;19:787 – 9.