Journal ofNeurology, Neurosurgery, and Psychiatry, 1978, 41, 1031-1035

Ewing's sarcoma of the spinal epidural space:report of two casesBERND W. SCHEITHAUER AND BARBARA M. EGBERT

From the Department of Pathology (Neuropathology), Stanford University School of Medicine,Stanford, California, and the Department of Pathology, Veterans Administration Hospital,Palo Alto, California, USA

SUMMARY Two new cases of primary extraosseous Ewing's sarcoma of the spinal epiduralspace, and their histogenesis and differential diagnosis are described. The diagnosis of Ewing'ssarcoma, which is essentially an undifferentiated tumour, depends largely on the exclusion ofseveral other neoplasms with morphological similarities. With these two cases, 43 extraosseousEwing's sarcomas have been reported to date, seven of which were epidural in location.

Most patients with Ewing's sarcoma present withthe clinical and radiographic features of a primaryosseous tumour. However, Tefft et al. (1969), in adiscussion of round cell tumours of the paraverte-bral region in children, described two patients withextraosseous paravertebral and contiguous epi-dural neoplasms with the morphological featuresof Ewing's sarcoma. Angervall and Enzinger (1975)subsequently established the entity of extraosseousEwing's sarcoma by describing 39 extraskeletalexamples. These occurred most frequently inyoung adults. Thirteen involved the paraspinalregion, and of these, three were epidural. Wereport an additional two patients with primaryextraosseous Ewing's sarcoma involving the spinalepidural space.

Case reports

CASE 1Two months before referral to the StanfordUniversity Medical Center, the patient, an 18year old Caucasian male student, complained ofradiating pain along the left iliac crest and anterioraspect of the thigh. This was followed one monthlater by low back pain which failed to respond tosymptomatic treatment. Physical examination onadmission disclosed focal tenderness to palpationover the L4-5 vertebral region. Although thepatient had complained of numbness and tingling

Address for reprint requests: Dr Bernd W. Scheithauer, Department ofPathology (Neuropathology), Stanford University Medical Center,Stanford, California 94305, USA.Accepted 23 June 1978

of the lateral aspect of the thigh, neurologicaltesting showed neither motor nor sensory loss.There was no bowel or bladder dysfunction. Lowback pain was worsened on straight leg raising.Radiography showed no osseous lesion, butdemonstrated complete myelographic block at theLI vertebral level. Laminectomy disclosed a softvascular circumscribed grey-tan tumour, 20 mmin width, compressing the left anterolateral surfaceof the dura mater at the LI vertebral level. Thetumour was completely resected; there was novisible bone involvement. Extensive postoperativeradiographic studies showed no other site oftumour. The patient received opposed anterior-posterior field radiation therapy to the thoraco-lumbar spine-5400 rads were administeredbetween the vertebral levels T12 to L2. Thereafter,pulse chemotherapy with vincristine, actinomycin-D, and cytoxan was given. The patient is freefrom disease without symptoms 16 months afterthe initial diagnosis.

CASE 2The patient, a 27 year old woman, first noted inco-ordination and increasing bilateral leg weaknessin the spring of 1967. One year later, increasinglysevere back pain, accompanied by bilateral legparaesthesiae, prompted radiographic studies whichdisclosed a paravertebral mass at the T6 ver-tebral level, associated with a complete extraduralblock at the vertebral levels T4-6. There was noradiographic evidence of bone involvement. Atlaminectomy, a paraspinal and partially epiduraldumb-bell shaped mass was found; neither com-

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ponent was excised totally. No vertebral or ribinvolvement was found. The patient received localradiation therapy (5000 rads), at the conclusionof which chest radiographs showed complete resol-ution of the paravertebral mass. The patient re-mained asymptomatic until June 1970, when shedeveloped increasingly severe back pain. Chestradiography in September 1970 showed a rightupper lobe mass and a mass in the right fifth rib,which was interpreted as a metastasis. Additionallocal radiation therapy and chemotherapy (vin-cristine, actinomycin-D, and cytoxan) were ad-ministered. In December 1970 there was noradiographic evidence of tumour and the patientwas asymptomatic. Chemotherapy was discon-tinued. The patient remained well during the nextfive years until December 1975, when radiographsdisclosed a lytic vertebral lesion. A thoracotomydisclosed tumour involving the vertebra and chestwall. A liver scan showed a pattern of diffuseparenchymal disease. The patient underwent 12monthly cycles of chemotherapy with the sameagents as before. Radiographic follow-up in Jan-uary 1978 showed near total resolution of thelesions.

PATHOLOGYBoth tumours consisted of a uniform populationof small round cells with pale indistinct cytoplasm.The cells, somewhat larger than lymphocytes,contained round to ovoid nuclei with distinctnuclear membranes, delicate, evenly dispersedchromatin, and small nucleoli. Mitotic figureswere numerous. The vesicular cytoplasm containedlarge quantities of PAS-positive, diastase-labileglycogen. Toluidine blue Nissl stained sectionsshowed no abnormality, and Bielschowsky silverimpregnation preparations showed no neurofibrils.The cells were disposed both in sheets (Fig. 1) andin irregular clusters, separated by fibrovascularsepta. Although small numbers of tumour cellswere enmeshed in a perivascular reticulin networkthat extended for a short distance from thesesepta, no reticulin fibres were present within thecellular sheets and lobules (Fig. 2). Some tumourcells tended to arrange themselves around capillaryblood vessels, but others showed a distinct ten-dency to rosette formation. This pattern wasreadily seen in numerous sections and was causedby the circumferential orientation of cells aroundminute foci of degenerating tumour cells (Fig. 3).Small numbers of cells with angular or elongatepyknotic nuclei and sparse eosinophilic cyto-plasm were also seen. These apparently degener-ating cells bore no consistent relationship to vessels(Fig. 4). Scattered macrophages with abundant

Fig 1 Case 1. Uniform population of small cellsdisposed in sheets. Haematoxylin-Van Gieson X 190.

Fig. 2 Case 1. Lobular arrangement of tumour cellswith lack of intercellular reticulin. Gordon-Sweets'silver method for reticulin X 190.

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cytoplasm were identified among the tumour cells.No production or invasion of bone or cartilage wasseen. Necrosis was patchy. No calcification wasfound.

Discussion

Hamby (1935, 1944), in an exhaustive literaturereview of intraspinal tumours of childhood, sum-marised 214 cases, of which 88 (41%) involved theepidural space. The relative frequency of tumourtypes in this location was as follows: sarcomas(39), schwannomas (11), chloromas (8), dermoidcysts (6), sympathetic tumours (5), vasculartumours (4), fibrous tumours (3), meningiomas (2),and lipomas (2). Four (10%) of the epiduralsarcomas demonstrated a contiguous paravertebralcomponent. By contrast, in the adult population,metastatic carcinoma from the lung or breast,lymphoma, and myeloma are the most frequentneoplasms involving the spinal epidural space. Inall series, most tumours affect the thoracic region,the lumbar level being the next most frequent. Noconsistent relationship exists between tumour type,primary site, and the level of cord compression.Ewing's sarcoma comprises 5% of the skeletal

tumours, occurs most frequently in males in thefirst to third decades, and, although it has beendescribed in nearly all the bones of the body,arises preferentially in the medullary cavity of thediaphysis of the tubular bones (Dahlin et al., 1961).Apart from absence of male sex predominance andfrom its occurrence in a slightly older age popula-tion (average 20 years), the biological behaviourand prognosis of extraosseous Ewing's sarcoma arevery similar to those of the skeletal examples.Tumours in both locations follow a rapid coursewith metastasis to lung and bone. Occasionally,Ewing's sarcoma may arise in the vertebral body,and encroach secondarily upon the epidural space(Anderson and Carson, 1953; Rand and Rand,1960), or sometimes the tumour may be situatedlargely in the periosteum and bone cortex. There-fore, it is essential to rule out vertebral involve-ment before making the diagnosis of extraosseousEwing's sarcoma.The histogenesis of Ewing's sarcoma has long

been a subject of debate. Whereas Ewing (1924),who noted the presence of tumour cells in vascularspaces, believed that the tumour arose from endo-thelial cells, subsequent authors have suggested anorigin from mesenchymal stem cells (Melnick,1922; Oberling and Raileanu, 1932), reticulumcells (Friedman and Gold, 1968; Takayama andSugawa, 1970) and primitive myeloid cells (Roomeand Delaney, 1932; Kadin and Bensch, 1971; Hou-

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Jensen et al., 1972). Kadin and Bensch (1971), in acombined electron microscopic and tissue culturestudy of a typical Ewing's sarcoma, reported theacquisition by tumour cells of hydrolytic enzymes,as well as azurophylic granules. They suggestedthat Ewing's tumour is a neoplasm of myelogenousorigin. Division of opinion also exists with regardto the nature of the dark cells in Ewing's sarcomaand their possible relationship to the more numer-ous light cells. On the basis of their ultrastructuralfeatures, Friedman and Gold (1968) regard thedark cells as more differentiated forms, withfeatures of reticulum cells, which arise throughtransitional forms from the light cells, which theyconsidered mesenchymal stem cells. A similarview is expressed by Nakayama et al. (1975). Kadinand Bensch (1971) regard the dark cells asdegenerating rather than as differentiated cells.The diagnosis of Ewing's sarcoma, which is

essentially an undifferentiated tumour, depends inlarge measure on the exclusion of several otherneoplasms with morphological similarities-that is,reticulum cell sarcoma (histiocytic lymphoma),neuroblastoma, alveolar rhabdomyosarcoma, andundifferentiated carcinoma. Abundant intra-cytoplasmic glycogen, the characteristic mor-phological feature of Ewing's sarcoma, isuncommon in neoplasms in general, and its demon-stration is crucial in the differential diagnosis. Theclinical importance and histological method ofdistinguishing reticulum cell sarcoma of bone fromEwing's sarcoma are discussed by Schajowicz(1959). Reticulum cell sarcoma (histiocyticlymphoma) lacks the lobular architecture ofEwing's sarcoma, has a variable quantity of inter-cellular reticulin, and is composed of larger cellswith vesicular nuclei and prominent nucleoli.PAS stains demonstrate little or no cytoplasmicglycogen, whereas the methyl green-pyronine stainfor ribonuclear protein is positive. Althoughpatients with neuroblastoma are frequentlyyounger than those with extraosseous Ewing's sar-coma and show involvement of the adrenal glandsor sympathetic ganglia, both lesions may presentwith epidural and contiguous paraspinal tumourinvolvement (Ingraham and Matson, 1954), andmay show rosettes on microscopy. Rosette forma-tion in Ewing's sarcoma has been describedpreviously (Foote and Anderson, 1941; Gharpure,1941). The rosettes of Ewing's sarcoma super-ficially resemble those of neuroblastoma, which inroutine sections stained with haematoxylin eosinshow no sharp luminal cell boundary, but ratherthe convergence of interlacing cell processes. Therosettes in our two cases of Ewing's sarcoma wereless well formed than those of neuroblastoma, and

Bernd W. Scheithauer and Barbara M. Egbert

were composed of tumour cells arranged aboutfoci of granular debris derived from degeneratingtumour cells. Bielschowsky silver impregnations,particularly when performed on frozen tissue,either fresh or fixed, should help in differentiatingthese "granular rosettes" from the fibrillarrosettes of Homer Wright.Comparative ultrastructural studies of Ewing's

sarcoma and neuroblastoma were performed byFriedman and Hanaoka (1971), and more recentlyby Nakayama et al. (1975). The cells of Ewing'ssarcoma were shown to contain abundant aggre-gated intracytoplasmic glycogen particles, whereasneuroblastoma cells demonstrated scattered densecore granules as well as processes containingneurofilaments and microtubules. The importanceof electron microscopy in the distinction of thesetwo tumours is underlined by the recent report ofa glycogen-containing neuroblastoma with clinicaland histopathological features of Ewing's sarcoma(Triche and Ross, 1978). The distinction of Ewing'ssarcoma from alveolar rhabdomyosarcoma is lessof a problem in that the latter is composed of lessuniform, darkly staining cells, possessing eosino-philic cytoplasm containing moderate quantities ofstored glycogen. Both cytoplasmic cross striationsand the distinct alveolar pattern with loss ofcentral cohesion are not seen in Ewing's sarcoma.The exclusion of undifferentiated carcinoma be-comes a consideration in older patients and mayrequire electron microscopy. The finding of wellformed desmosomes with tonofilaments, acharacteristic of epithelial cells, confirms thediagnosis. The demonstration of specific granulesand enzyme histochemical reactions peculiar toacute leukaemic infiltrates should facilitate theirdistinction from Ewing's sarcoma.We have presented two further cases of primary

extraosseous Ewing's sarcoma, both involving theepidural space. Although the follow-up is rathershort, the disease-free course of case 1 is ex-ceptional and is likely to reflect the completenessof surgical excision as well as the efficacy ofaggressive irradiation and sequential adjuvantchemotherapy as recommended by Rosen et al.(1978). The late recurrence and prolonged courseof the disease in case 2 is also unusual, but thedevelopment of pulmonary and osseous meta-stases is characteristic of Ewing's sarcoma.With the inclusion of these cases, 43 extraosseous

Ewing's sarcomas have been reported to date(Tefft et al., 1969; Angerval and Enzinger, 1975);seven (17%) were epidural in location, three of thesewere contiguous with, and may represent extensionfrom, tumour in the paravertebral area. Six of theseven cases involved the thoracolumbar region.

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This study was supported in part by GraduateNeuropathology Training Grant 5 TOI NS-05500-11 of the National Institute of Neurological andCommunicative Diseases and Stroke, USPHS. Wewould like to thank Dr L. S. Hurwitz and Dr W. V.Dolan, Milwaukee, Wisconsin for making thematerial of case 2 available to us, and Dr L. J.Rubinstein and Dr H. Urich for critical review ofthe manuscript.

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