Primary Intraspinal Primitive Neuroectodermal Tumor (PNET) : A

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

M.J.Virani, S. Jain

Department of NeurosurgeryJaslok Hospital and Research Centre

Mumbai - 400 026, India.

Summary

The concept of primitive neuroectodermal tumors (PNETs) has been evolving for manyyears, as has been its nomenclature. A 5 year old boy presented with pain in lowercervicodorsal region and left leg. Preoperative MRI of the spine and paravertebral regionrevealed a hyperintense lobulated lesion extending from D1-D4 with a large intraspinaland thoracic component. A total removal of tumor was achieved via a dorsal laminectomyand right posterolateral thoracotomy. The pathological findings were consistent withPNET. Post operative neurological examination had been unremarkable. Six months followup scan showed no recurrence. A review of the literature shows that only 18 cases ofprimary intraspinal PNETs have been reported to date and the present case is exclusive, inwhich the tumor was thoracic, extradural in location and the child is alive at 8 months offollow up, with no evidence of tumor recurrence/metastasis. Primary intraspinal PNETsare rare tumors and carry a poor prognosis. Newer modalities of treatment should be triedto 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 termproposed by Hart and Earle defines a group ofmalignant neoplasms of presumed neural crestorigin.1 Cases of PNET have been increasinglyreported in recent years but there are still very fewreports of PNET originating in the spinal cord.

To date, only 18 cases of primary intraspinal PNETshave been reported in the literature. The clinical andpathological features of PNET, its management, andperspectives for the future, with reference to a case ofPNET of the spinal cord, are discussed.

Case Report

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

75Neurology India, 50, March 2002

Correspondence to : Dr. M.J. Virani, 100, AA, SeaView,Bholabhai Desai Road, Mumbai 400 026, India.E mail : [email protected]

CASE REPORT

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Primary Intraspinal Primitive Neuroectodermal Tumor

Neurology India, 50, March 2002

lethargy of one month duration. Family history wasunremarkable. There was no history of sphinctericdisturbances, weight loss and gait disturbances. Onexamination, vital parameters were normal. Minimalthoracic scoliosis to right was observed. Neurologicalexamination was unremarkable except for theunsteady gait and tendency to sway to right side.Finger-nose and toe-heel tests were normal.

Radiographic investigations : X-ray chest revealed aheterogeneous soft tissue shadow in right upper zoneand right paraspinal region with a smooth convexborders with apparent widening of right 3rdintercostal space posteriorly. Pneumonicconsolidation or posterior mediastinal mass wereconsidered as possibilities. MRI of the spine andparavertebral region revealed a hyperintense lobulatedlesion in paravertebral region extending from D1-D4with a large intraspinal and thoracic component.Spinal cord was pushed completely to the left by thelesion (Fig. 1).

Operation : In view of MRI appearance of the tumorhemilaminectomy from C7 to D1 on right side wasperformed along with right posterolateralthoracotomy. The tumor was extradural in origin andwas compressing the cord. Following surgeryintercostal tube was inserted to preventpneumothorax. Postsurgery good chest expansion wasnoted. Gross total removal of the tumor wasperformed under the operating microscope.

Pathological findings : Tissue specimen represented afocally necrotic undifferentiated malignant tumorconsisting of small round cells exhibiting little or nocytoplasm and rounded smooth contoured vesicular or

dense hyperchromatic actively mitotic nuclei. Cellswere arranged in compact pattern. No well-definedHomer-Wright or ependymal rosettes were noted(Fig. 2). Immunohistochemistry was performed usingthe primary antibodies : synoptophysin, (Dako corp.),LCA and Cytokeratin. Tumor cells showed granularimmunostaining in the cytoplasmic rim withsynoptophysin. Cytokeratin, LCA were absent in the

Fig. 1 : Preoperative MRI : (A) Axial view at D2-D3 level; T2WI showing extradural heterogeneous mass lesions eroding thepedicle and posterior part of the body. (B) Sagittal views : (T1WI) (C) (T2WI) showing intraspinal component extending fromD1-D4 vertebral levels compressing and displacing the thecal sac and the spinal cord.

Fig. 1d : Coronal view; T2WI showing the ‘dumbbell’ typeextension of the lesion from the spinal canal through the rightD2-3 intervertebral foramen into the mediastinum,compressing upper zone of the right lung.

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tumor. Electron microscopy confirmed the presence ofpoorly differentiated small round cells.The diagnosisof a PNET was arrived at after histologicalexamination, immunohistochemistry and electronmicroscopy.

Postoperative course : Postoperative course had beenuneventful. CT scan brain was normal. Post surgeryneurological status showed a slightly weak right grip,unsteady gait which improved with gait training andphysiotherapy. A thoracic chin occiput brace wasprovided. Following surgical recovery, radiationtherapy was given in the form of involved fieldirradiation (IFI) for a period of 8 weeks. MRI at theconclusion of radiotherapy failed to reveal anyrecurrence or metastasis (Fig. 3). Currently, eightmonths after surgery he was asymptomatic, walkedunsupported, and had no neurological deficits.

Discussion

PNETs are rapidly growing tumors with a briefduration of symptoms and a rapidly progressivecourse.1 The tumors encountered are difficult toclassify.2 It was first described as a tumor arising inperipheral nerve, and was called neuroepithelioma.3

Hart and Earle first introduced the term primitiveneuroectodermal tumor in 1973 to describepredominantly undifferentiated tumors of thecerebrum (with 90-95% of the cells beingundifferentiated) that did not fulfill the diagnosticcriteria for neuroblastoma, ependymoblastoma, polarspongioblastoma, medulloepithellioma or pinealparenchyma tumors. All neoplasm showing primitivepoorly differentiated neuroepithelial cellls can becalled primitive neuroectodermal tumors, regardlessof location or cell type.2,5 Relationship of PNETs andother central nervous system neoplasms is shown inFig. 4. In 1983, Rorke6 and Becker and Hinton7

independently reviewed this concept and publishedseparate articles advocating that all central nervoussystem tumors predominantly composed of primitiveneuroepithelial cells be called PNETs. They thenfurther subclassified these tumors based ondifferentiation. This concept has been widelyaccepted, although it is still controversial. The mostrecent classification by world health organization triesto avoid this controversy by grouping these tumorsunder the category of ‘embryonal tumors’ with PNETused as a generic term for cerebellar medullo-blastomas.8

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

Fig. 3a and b : Postoperative MRI in sagittal projection inT1WI and T2WI showing complete excision of the lesion fromthe spinal canal and the posterior mediastinum.

PNETs most commonly occur in the cerebellum(medulloblastoms) but can arise in the pineal gland,cerebrum, spinal cord brain stem, and peripheralnerves.9 Primitive neuroectodermal tumors frequentlymetastasize via the CSF pathways to the spinal andcranial subarachnoid spaces and are highly malignantboth histologically and clinically.10 Standard therapyfor the PNET currently consists of gross totalresection followed by craniospinal irradiation.Radiation is associated with a higher incidence ofintellectual impairment endocrinological distur-bances, and growth retardation in young children andresults in 5 year survival rates of only 40% to 60%.Chemotherapy is the sole form of therapy used inchildren under two years of age, because of severeside effects of irradiation in this age group.10 Becausesurgery, irradiation and chemotherapy do notadequately treat PNET additional treatmentmodalities need to be explored.

The 18 previously reported cases along with presentcase are summarized in Table I. In most of these cases,efforts were made to exclude primary intracraniallesions either by imaging and/or autopsy. In presentcase, the extradural location makes it unlikely that thisis a drop metastasis. Morever, CT scan of head failedto reveal any intracranial tumor. This case thereforeappears to be exclusive and represents a primarythoracic spinal cord PNET, as neither cerebral norcerebellar intra-axial lesion, nor peripheralneuroblatomas were seen.

A review of literature shows that primary intraspinalPNETs may arise at all levels of the spine and can beintramedullary, intra - and extramedullary,extramedullary or extradural. It has been postulatedthat PNETs arise from neoplastic transformation ofprimitive neuroepithelial cells in subependymalzones.6 The clinical characteristics of spinal PNETs inthe cases described so far including ours (Table I)appear to be:- i) more common in adults rather thanchildren. 12 out of 19 cases being adults, ii) maleswere predominnantly affected, iii) some of thereported cases had metastasis outside neuraxis withthe most frequent sites being lung, bones and

lymphnodes, a tendency shared by intracranialPNETs,2,11,14 iv) most of the patients were treatedwith a combination of surgery, radiotherapy andchemotherapy, but despite treatment most patients didnot do well, v) extremely short duration of symptomsfavour rapidly growing nature of these tumors, vi) theaggressive nature of the tumor is evidenced by rapidrecurrence of the tumor in most of the reportedpatients. The cause of death in these patients includedpneumonia,12 metastatic disease,14 aggressive localspread of the diseased,18 and progressive spinal cordinvolvement.16 vii) the tumor was frequently locatedat lower spinal levels : cervical in four cases, thoracicin two, thoracolumbar in four, lumbar/lumbosacral in7 cases. viii) as expected in rapidly growing tumorssuch as these, the survival is less than 2 years. Lessthan 40% of these patients were alive 2 year afterdiagnosis, about 10% at 3 year (Fig. 5). Therefore,need for newer therapeutic modality to improve thesurvival in these cases.

PET with ‘8F-fluoro-2-deoxy-glucose (FDG) is aneffective imaging modality for evaluating suspectedtumor recurrence. Use of FDG PET imaging for spinalcord neoplasms has not yet been studied, mainly dueto limitations of spatial resolution. Cidis et al22

demonstrated the role of FDG PET imaging inrecurrent intramedullary PNET affecting the cervicalspinal cord.

Adoptive immunotherapy is currently beinginvestigated as a possible therapy. Lymphokine -activated killer cells possess several attributes thatcould make them useful in adoptive immunotherapy.They are highly potent against tumors, require noprior antigen exposure to express their oncolyticeffect. Their recognition mechanism is able todistinguish between normal and malignant cells andthereby spare normal tissue and they express oncolytic

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

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

activity against many tumour types.10 This study wasunder taken by Richard et al10 to determine thepotential sensitivity to the tumor cells derived fromPNET. The results presented in this study support anadoptive immunotherapeutic approach, consisting ofintrathecal administration of IL-2 and LAK cells asan adjuvant to the treatment of PNET. This form oftherapy could eradicate residual tumour without theharmful side effects that radiation or chemotherapyproduce. The optimal therapy for PNET is uncertain.Early onset of chemotherapy17,23 in conjunction withradiation therapy may improve the survival time.However the prognosis of this disease is very poor andmost 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 incases where the patient has remissions. PBSCT afterremissions prevents relapse. A trial has beenconducted at Hinduja hospital, Mumbai, India, wherePBSCT was employed in 21 year old male with PNETof chest wall-stage-IV. More studies are required toexplore the role of PBSCT in improving the survival

in these patients.24 Based on this review, we concludethat future advances in the treatment of PNETs mustlie with chemotherapy and immunotherapy especiallyfor those patients presenting with disseminateddisease. This, combined with early detection, tumoridentification and surgical removal and aggressiveneuraxis radiation, offers hope of long term and goodquality survival. It is fascinating that a tumor whichmay be of embryonic origin can remain latent andbecome manifest many years later, suggestingdifferences in biology involving the tumor itself or thehost.

References

1. Barbara J : Crain. Primitive neuroectodermal tumours. In :Neurosurgery by Rengachary, Robert H. Wilkins 1996; Vol.II : 1707-1713.

2. Edward J kosnik, Carl Boesel, Janet Bay et al : Primitiveneuroectodermal tumours of the central nervous system inthe children. J Neurosurg 1978; 48 : 741-746.

3. Von Schlippe M, Whelan JS et al : Primitive neuroectodermaltumour of the chest wall. Ann Oncol 1995; 6/4 : 395-401.

4. Hart MN, Earle KM : Primitive neuroectodermal tumours ofthe brain in children. Cancer 1973; 32 : 890-897.

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Table I

Summary of the Reported Cases of PNET-Spinal Cord

Patient Series Age/Sex Level Location Metastasis Survival No. (months)

1 Smith et al11 24 M Lumbar Cauda equina Lung 102. Kosnik et al2 <10/NA Cervical Unknown None ?<243. ,, <10/NA Cervical Unknown None ?<244. ,, <10/NA Thoracolumbar Unknown Lung,bone, ?<24

lymph node5. Kepes et al12 24 M Lumbar Cauda equina None 186. ,, 56 M Lumbar Cauda equina None Alive at 367. ,, 39 M Lumbar Cauda equina None 428. Liu et al13 26 F Lumbosacral Extradural None Alive at 69. Sevick et al14 26 M Cervical Intra dural Pleura, bone, 36

extramedullary lymph nodes10. Jakse et al15 15 F Thoracolumbar Intra and None 18

extramedullary11. ,, 26 M Lumbar/thoracic Cauda equina/intra None 36

and extramedullary12. Freyer et al16 7 M Thoracolumbar Intramedullary None 2013. Ogasawara et al13 16 F Lumbar Intramedullary Intracranial 2914. McDermott et al17 47 M Lumbar Cauda equina None 1615. Kwon et al18 3mths F Midthoracic Intramedullary Intracranial <116. Deme et al19 22 F Thoracolumbar Intramedullary None Alive at 1517. Koot et al20 2 F Cervical - - < 118. Rodriquez et al21 16 M - - - -19. Present case 4 M Thoracic+ Extradural None Alive at 8

mediastinal

5. Vincent T, De Vita, Jr Samuel Hellman : Neoplasms of thecentral nervous system. In : Cancer-Principles and practiceof oncology. 1997; 5 : 2059-2060.

6. Rorke LB : The cerebellar medulloblastoma and itsrelationship to primitive neuroectodermal tumours.J Neuropath Exp Neurol 1983; 42 : 1-15.

7. Backer A, Mount S L, Zarka MA et al Desmoplastic roundcell primary tumour of unknown origin with lymph nodes andlung metastases : Histological, cytological, ultrastructural,cytogenetic and molecular findings. In Virchows Arch.432/2(135-141); 1998.

8. Kielhuer P, Bueger PC, Scheithauer BW : The new WHOclassification of brain tumours. Brain Pathol 1993; 3 : 255-268.

9. Srikanth Deme, Lee-cyn, Ghassan S et al : Primaryintramedullary primitive neuroectodermal tumour of thespinal cord : case report and review of the literatureNeurosurgery 1997; 41 : 1417-1420.

10. Richard, William, Richard Moser et al : Invitro cytolysis ofprimitive neuroectodermal tumours of the posterior fossa(medulloblastoma) by lymphokine activated killer cells.J Neurosurg 1988; 60 : 403-409.

11. Smith DR, Hardman JM, Earle KM et al : Metastasizingneuroectodermal tumours of the central nervous system.J Neurosurg 1969; 31 : 50-58.

12. Kepes JJ, Belton K, Roessmann U et al : Primitiveneuroectodermal tumours of the cauda equina in adults withno detectable primary intracranial neoplasm : Three casestudies. Clin Neuropathol 1985; 4 : 1-11.

13. Liu HM, Yang WC, Garcia RL et al : Intraspinal primitiveneuroectodermal tumour arising from the sacral neve root.J Comput Tomogr 1987; 11 : 350-354.

14. Sevick RJ, Johns RD, Curry BJ et al : Primary spinalneuroectodermal tumour with extraneural metastasis. AJNR1987; 8 : 1151-1152.

15. Jakshe H, Wockel W, Wernert N : Primary spinalmedulloblastomas? Neurosurg Rev 1988; 11 : 259-265.

16. Freyer DR, Hutchinson RJ, McKeever PE : Primary primitiveneuroectodermal tumour of the spinal cord associated withneural tube defect. Pediatric Neurosci 1989; 15 : 181-187.

17. Ogaswara H, Kiva K, Kurisu K et al : Intracranial metastasisfrom a spinal cord primitive neuroectodermal tumour : casereport. Surg Neurol 1992; 37 : 307-312.

18. McDermott VG, El-Jabbour, Sellar RJ et al : Primitiveneuroectodermal tumour of the cauda equina.Neuroradiology 1994; 36 : 228-230.

19. Kwon OK, Wang KC, Ki IO et al : Primary intramedullaryspinal cord primitive neuroectodermal tumour withintracranial seeding in an infant. Child’s Nerv Syst 1996; 12: 633-636.

20. Koot RW, Henneveld H, Albrecht K et al : Two children withunusual causes of torticollis: Primitive neuroectoddermaltumour and Grisel’s syndrome. Ned Tijdschr Geneeskd1998; 142 : 1030-1033.

21. Rodriguez ku RJ, Trejo Castillo W, Rodriguez ML et al :Spinal primitive neuroectodermal tumour. Gac Med Mex1999; 135 : 183-188.

22. Cidis C, David M,Townsend W et al : FDG imaging of spinalcord primitive neuroectodermal tumour. J Nucl Med 1998; 39: 1207-1209.

23. Rivera-Luna R, Gomez R, Leal C et al : Is the ancillarychemotherapy approach of any value in the treatment ofinfratentorial primitive neuroectodermal tumours with surgeryand 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.

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Accepted for publication : 18th December, 2000.

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Primary Intraspinal Primitive Neuroectodermal Tumor (PNET) : A