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CASE REPORT

Primary Intraspinal Primitive Neuroectodermal Tumor (PNET) : A Rare Occurrence

M.J.Virani, S. Jain

Department of Neurosurgery Jaslok Hospital and Research Centre Mumbai - 400 026, India.

Summary

The concept of primitive neuroectodermal tumors (PNETs) has been evolving for many years, as has been its nomenclature. A 5 year old boy presented with pain in lower cervicodorsal region and left leg. Preoperative MRI of the spine and paravertebral region revealed a hyperintense lobulated lesion extending from D1-D4 with a large intraspinal and thoracic component. A total removal of tumor was achieved via a dorsal laminectomy and right posterolateral thoracotomy. The pathological findings were consistent with PNET. Post operative neurological examination had been unremarkable. Six months follow up scan showed no recurrence. A review of the literature shows that only 18 cases of primary intraspinal PNETs have been reported to date and the present case is exclusive, in which the tumor was thoracic, extradural in location and the child is alive at 8 months of follow up, with no evidence of tumor recurrence/metastasis. Primary intraspinal PNETs are rare tumors and carry a poor prognosis. Newer modalities of treatment should be tried to improve survival.

Key words : Spinal cord, Primitive neuroectodermal tumor (PNET), Radiation,

Chemotherapy, Immunotherapy.

Neurol India, 2002; 50 : 75-80

Introduction

Primary neuroectodermal tumor (PNET), a term proposed by Hart and Earle defines a group of malignant neoplasms of presumed neural crest origin.1 Cases of PNET have been increasingly reported in recent years but there are still very few reports of PNET originating in the spinal cord.

Correspondence to : Dr. M.J. Virani, 100, AA, Sea View,Bholabhai Desai Road, Mumbai 400 026, India. E mail : [email protected] Neurology India, 50, March 2002

To date, only 18 cases of primary intraspinal PNETs have been reported in the literature. The clinical and pathological features of PNET, its management, and perspectives for the future, with reference to a case of PNET of the spinal cord, are discussed.

Case Report

A previously healthy 5 year old male child presented with complaints of lower cervico-dorsal pain, breathlessness on exertion, pain in left leg, lassitude,

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Primary Intraspinal Primitive Neuroectodermal Tumor

Fig. 1 : Preoperative MRI : (A) Axial view at D2-D3 level; T2WI showing extradural heterogeneous mass lesions eroding the pedicle and posterior part of the body. (B) Sagittal views : (T1WI) (C) (T2WI) showing intraspinal component extending from D1-D4 vertebral levels compressing and displacing the thecal sac and the spinal cord.

lethargy of one month duration. Family history was unremarkable. There was no history of sphincteric disturbances, weight loss and gait disturbances. On examination, vital parameters were normal. Minimal thoracic scoliosis to right was observed. Neurological examination was unremarkable except for the unsteady gait and tendency to sway to right side. Finger-nose and toe-heel tests were normal. Radiographic investigations : X-ray chest revealed a heterogeneous soft tissue shadow in right upper zone and right paraspinal region with a smooth convex borders with apparent widening of right 3rd intercostal space posteriorly. Pneumonic consolidation or posterior mediastinal mass were considered as possibilities. MRI of the spine and paravertebral region revealed a hyperintense lobulated lesion in paravertebral region extending from D1-D4 with a large intraspinal and thoracic component. Spinal cord was pushed completely to the left by the lesion (Fig. 1). Operation : In view of MRI appearance of the tumor hemilaminectomy from C7 to D1 on right side was performed along with right posterolateral thoracotomy. The tumor was extradural in origin and was compressing the cord. Following surgery intercostal tube was inserted to prevent pneumothorax. Postsurgery good chest expansion was noted. Gross total removal of the tumor was performed under the operating microscope. Pathological findings : Tissue specimen represented a focally necrotic undifferentiated malignant tumor consisting of small round cells exhibiting little or no cytoplasm and rounded smooth contoured vesicular or

Fig. 1d : Coronal view; T2WI showing the `dumbbell' type extension of the lesion from the spinal canal through the right D2-3 intervertebral foramen into the mediastinum, compressing upper zone of the right lung.

dense hyperchromatic actively mitotic nuclei. Cells were arranged in compact pattern. No well-defined Homer-Wright or ependymal rosettes were noted (Fig. 2). Immunohistochemistry was performed using the primary antibodies : synoptophysin, (Dako corp.), LCA and Cytokeratin. Tumor cells showed granular immunostaining in the cytoplasmic rim with synoptophysin. Cytokeratin, LCA were absent in the

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Fig. 3a and b : Postoperative MRI in sagittal projection in T1WI and T2WI showing complete excision of the lesion from the spinal canal and the posterior mediastinum.

Discussion

PNETs are rapidly growing tumors with a brief duration of symptoms and a rapidly progressive course.1 The tumors encountered are difficult to classify.2 It was first described as a tumor arising in peripheral nerve, and was called neuroepithelioma.3 Hart and Earle first introduced the term primitive neuroectodermal tumor in 1973 to describe predominantly undifferentiated tumors of the cerebrum (with 90-95% of the cells being undifferentiated) that did not fulfill the diagnostic criteria for neuroblastoma, ependymoblastoma, polar spongioblastoma, medulloepithellioma or pineal parenchyma tumors. All neoplasm showing primitive poorly differentiated neuroepithelial cellls can be called primitive neuroectodermal tumors, regardless of location or cell type.2,5 Relationship of PNETs and other central nervous system neoplasms is shown in Fig. 4. In 1983, Rorke6 and Becker and Hinton7 independently reviewed this concept and published separate articles advocating that all central nervous system tumors predominantly composed of primitive neuroepithelial cells be called PNETs. They then further subclassified these tumors based on differentiation. This concept has been widely accepted, although it is still controversial. The most recent classification by world health organization tries to avoid this controversy by grouping these tumors under the category of `embryonal tumors' with PNET used as a generic term for cerebellar medulloblastomas.8

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Fig. 2 : Photomicrographs of the spinal PNET showing undifferentiated small round cells with little or no cytoplasm and dense hyperchromatic actively mitotic nuclei [haematoxylin and eosin ; original magnification a) -x10, b) x 40]

tumor. Electron microscopy confirmed the presence of poorly differentiated small round cells.The diagnosis of a PNET was arrived at after histological examination, immunohistochemistry and electron microscopy. Postoperative course : Postoperative course had been uneventful. CT scan brain was normal. Post surgery neurological status showed a slightly weak right grip, unsteady gait which improved with gait training and physiotherapy. A thoracic chin occiput brace was provided. Following surgical recovery, radiation therapy was given in the form of involved field irradiation (IFI) for a period of 8 weeks. MRI at the conclusion of radiotherapy failed to reveal any recurrence or metastasis (Fig. 3). Currently, eight months after surgery he was asymptomatic, walked unsupported, and had no neurological deficits.

Neurology India, 50, March 2002

Primary Intraspinal Primitive Neuroectodermal Tumor

Fig. 4 : Relationship of PNETs and other neoplasms of the central nervous system .

PNETs most commonly occur in the cerebellum (medulloblastoms) but can arise in the pineal gland, cerebrum, spinal cord brain stem, and peripheral nerves.9 Primitive neuroectodermal tumors frequently metastasize via the CSF pathways to the spinal and cranial subarachnoid spaces and are highly malignant both histologically and clinically.10 Standard therapy for the PNET currently consists of gross total resection followed by craniospinal irradiation. Radiation is associated with a higher incidence of intellectual impairment endocrinological disturbances, and growth retardation in young children and results in 5 year survival rates of only 40% to 60%. Chemotherapy is the sole form of therapy used in children under two years of age, because of severe side effects of irradiation in this age group.10 Because surgery, irradiation and chemotherapy do not adequately treat PNET additional treatment modalities need to be explored. The 18 previously reported cases along with present case are summarized in Table I. In most of these cases, efforts were made to exclude primary intracranial lesions either by imaging and/or autopsy. In present case, the extradural location makes it unlikely that this is a drop metastasis. Morever, CT scan of head failed to reveal any intracranial tumor. This case therefore appears to be exclusive and represents a primary thoracic spinal cord PNET, as neither cerebral nor cerebellar intra-axial lesion, nor peripheral neuroblatomas were seen. A review of literature shows that primary intraspinal PNETs may arise at all levels of the spine and can be intramedullary, intra - and extramedullary, extramedullary or extradural. It has been postulated that PNETs arise from neoplastic transformation of primitive neuroepithelial cells in subependymal zones.6 The clinical characteristics of spinal PNETs in the cases described so far including ours (Table I) appear to be:- i) more common in adults rather than children. 12 out of 19 cases being adults, ii) males were predominnantly affected, iii) some of the reported cases had metastasis outside neuraxis with the most frequent sites being lung, bones and

Fig. 5 : Survival curve of the 18 reported patients of intraspinal PNET.

lymphnodes, a tendency shared by intracranial PNETs,2,11,14 iv) most of the patients were treated with a combination of surgery, radiotherapy and chemotherapy, but despite treatment most patients did not do well, v) extremely short duration of symptoms favour rapidly growing nature of these tumors, vi) the aggressive nature of the tumor is evidenced by rapid recurrence of the tumor in most of the reported patients. The cause of death in these patients included pneumonia,12 metastatic disease,14 aggressive local spread of the diseased,18 and progressive spinal cord involvement.16 vii) the tumor was frequently located at lower spinal levels : cervical in four cases, thoracic in two, thoracolumbar in four, lumbar/lumbosacral in 7 cases. viii) as expected in rapidly growing tumors such as these, the survival is less than 2 years. Less than 40% of these patients were alive 2 year after diagnosis, about 10% at 3 year (Fig. 5). Therefore, need for newer therapeutic modality to improve the survival in these cases. PET with `8F-fluoro-2-deoxy-glucose (FDG) is an effective imaging modality for evaluating suspected tumor recurrence. Use of FDG PET imaging for spinal cord neoplasms has not yet been studied, mainly due to limitations of spatial resolution. Cidis et al22 demonstrated the role of FDG PET imaging in recurrent intramedullary PNET affecting the cervical spinal cord. Adoptive immunotherapy is currently being investigated as a possible therapy. Lymphokine activated killer cells possess several attributes that could make them useful in adoptive immunotherapy. They are highly potent against tumors, require no prior antigen exposure to express their oncolytic effect. Their recognition mechanism is able to distinguish between normal and malignant cells and thereby spare normal tissue and they express oncolytic

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Table I Summary of the Reported Cases of PNET-Spinal Cord Patient No. 1 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Series Age/Sex Level Location Metastasis Survival (months) 10 ?<24 ?<24 ?<24 18 Alive at 36 42 Alive at 6 36 18 36 20 29 16 <1 Alive at 15 <1 Alive at 8

Smith et al11 Kosnik et al2 ,, ,, Kepes et al12 ,, ,, Liu et al13 Sevick et al14 Jakse et al15 ,, Freyer et al16 Ogasawara et al13 McDermott et al17 Kwon et al18 Deme et al19 Koot et al20 Rodriquez et al21 Present case

24 M <10/NA <10/NA <10/NA 24 56 39 26 26 M M M F M

Lumbar Cervical Cervical Thoracolumbar Lumbar Lumbar Lumbar Lumbosacral Cervical

Cauda equina Unknown Unknown Unknown

15 F 26 M 7M 16 F 47 M 3mths F 22 F 2F 16 M 4M

Cauda equina Cauda equina Cauda equina Extradural Intra dural extramedullary Thoracolumbar Intra and extramedullary Lumbar/thoracic Cauda equina/intra and extramedullary Thoracolumbar Intramedullary Lumbar Intramedullary Lumbar Cauda equina Midthoracic Intramedullary Thoracolumbar Intramedullary Cervical Thoracic+ Extradural mediastinal

Lung None None Lung,bone, lymph node None None None None Pleura, bone, lymph nodes None None None Intracranial None Intracranial None None

activity against many tumour types.10 This study was under taken by Richard et al10 to determine the potential sensitivity to the tumor cells derived from PNET. The results presented in this study support an adoptive immunotherapeutic approach, consisting of intrathecal administration of IL-2 and LAK cells as an adjuvant to the treatment of PNET. This form of therapy could eradicate residual tumour without the harmful side effects that radiation or chemotherapy produce. The optimal therapy for PNET is uncertain. Early onset of chemotherapy17,23 in conjunction with radiation therapy may improve the survival time. However the prognosis of this disease is very poor and most patients develop local recurrence. As regard to new treatment strategies are concerned, role of peripheral blood stem cell transfusion (PBSCT) is suggested in chemosensitive tumors or in cases where the patient has remissions. PBSCT after remissions prevents relapse. A trial has been conducted at Hinduja hospital, Mumbai, India, where PBSCT was employed in 21 year old male with PNET of chest wall-stage-IV. More studies are required to explore the role of PBSCT in improving the survival

in these patients.24 Based on this review, we conclude that future advances in the treatment of PNETs must lie with chemotherapy and immunotherapy especially for those patients presenting with disseminated disease. This, combined with early detection, tumor identification and surgical removal and aggressive neuraxis radiation, offers hope of long term and good quality survival. It is fascinating that a tumor which may be of embryonic origin can remain latent and become manifest many years later, suggesting differences in biology involving the tumor itself or the host.

References

1. Barbara J : Crain. Primitive neuroectodermal tumours. In : Neurosurgery by Rengachary, Robert H. Wilkins 1996; Vol. II : 1707-1713. Edward J kosnik, Carl Boesel, Janet Bay et al : Primitive neuroectodermal tumours of the central nervous system in the children. J Neurosurg 1978; 48 : 741-746. Von Schlippe M, Whelan JS et al : Primitive neuroectodermal tumour of the chest wall. Ann Oncol 1995; 6/4 : 395-401. Hart MN, Earle KM : Primitive neuroectodermal tumours of the brain in children. Cancer 1973; 32 : 890-897.

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Vincent T, De Vita, Jr Samuel Hellman : Neoplasms of the central nervous system. In : Cancer-Principles and practice of oncology. 1997; 5 : 2059-2060. Rorke LB : The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumours. J Neuropath Exp Neurol 1983; 42 : 1-15. Backer A, Mount S L, Zarka MA et al Desmoplastic round cell primary tumour of unknown origin with lymph nodes and lung metastases : Histological, cytological, ultrastructural, cytogenetic and molecular findings. In Virchows Arch.432/2 (135-141); 1998. Kielhuer P, Bueger PC, Scheithauer BW : The new WHO classification of brain tumours. Brain Pathol 1993; 3 : 255268. Srikanth Deme, Lee-cyn, Ghassan S et al : Primary intramedullary primitive neuroectodermal tumour of the spinal cord : case report and review of the literature Neurosurgery 1997; 41 : 1417-1420. Richard, William, Richard Moser et al : Invitro cytolysis of primitive neuroectodermal tumours of the posterior fossa (medulloblastoma) by lymphokine activated killer cells. J Neurosurg 1988; 60 : 403-409. Smith DR, Hardman JM, Earle KM et al : Metastasizing neuroectodermal tumours of the central nervous system. J Neurosurg 1969; 31 : 50-58. Kepes JJ, Belton K, Roessmann U et al : Primitive neuroectodermal tumours of the cauda equina in adults with no detectable primary intracranial neoplasm : Three case studies. Clin Neuropathol 1985; 4 : 1-11. Liu HM, Yang WC, Garcia RL et al : Intraspinal primitive neuroectodermal tumour arising from the sacral neve root. J Comput Tomogr 1987; 11 : 350-354. Sevick RJ, Johns RD, Curry BJ et al : Primary spinal neuroectodermal tumour with extraneural metastasis. AJNR 1987; 8 : 1151-1152.

15. Jakshe H, Wockel W, Wernert N : Primary spinal medulloblastomas? Neurosurg Rev 1988; 11 : 259-265. 16. Freyer DR, Hutchinson RJ, McKeever PE : Primary primitive neuroectodermal tumour of the spinal cord associated with neural tube defect. Pediatric Neurosci 1989; 15 : 181-187. 17. Ogaswara H, Kiva K, Kurisu K et al : Intracranial metastasis from a spinal cord primitive neuroectodermal tumour : case report. Surg Neurol 1992; 37 : 307-312. 18. McDermott VG, El-Jabbour, Sellar RJ et al : Primitive neuroectodermal tumour of the cauda equina. Neuroradiology 1994; 36 : 228-230. 19. Kwon OK, Wang KC, Ki IO et al : Primary intramedullary spinal cord primitive neuroectodermal tumour with intracranial seeding in an infant. Child's Nerv Syst 1996; 12 : 633-636. 20. Koot RW, Henneveld H, Albrecht K et al : Two children with unusual causes of torticollis: Primitive neuroectoddermal tumour and Grisel's syndrome. Ned Tijdschr Geneeskd 1998; 142 : 1030-1033. 21. Rodriguez ku RJ, Trejo Castillo W, Rodriguez ML et al : Spinal primitive neuroectodermal tumour. Gac Med Mex 1999; 135 : 183-188. 22. Cidis C, David M,Townsend W et al : FDG imaging of spinal cord primitive neuroectodermal tumour. J Nucl Med 1998; 39 : 1207-1209. 23. Rivera-Luna R, Gomez R, Leal C et al : Is the ancillary chemotherapy approach of any value in the treatment of infratentorial primitive neuroectodermal tumours with surgery and radiotherapy? Child's Nerv Syst 1998; 14 : 109-112. 24. Soumya V : Hinduja successfully performs its first PBSCT. In : Express Healthcare Management 2000; 1 : 3.

Accepted for publication : 18th December, 2000.

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