Neoplasms of mixed mesenchymal and neuroepithelial type With consideration of the relationship between meningioma and neurilemmoma

,~ore'n,1/o~ the ncuro]o!lica/ Sciem'c.~ I!l,,e','ler Publishing Company, Amsterdam

Printed in The Nctherland ~,

277

Neoplasms of Mixed Mesenchymal and Neuroepithelial

Type With Consideration of the Relationship between Meningioma and Neurilernmoma S. S H U A N G S H O T I * ,

M. G. N E T S K Y AND J. A. J A N E

Department o[" Pathok~.qv, Universi O' q[" l,Trginia School o f Medicine, CharlottesHlle, Ira. 22903 ( U.S.A. ,' (Received 23 February, 1971)

INTROI)U('TION

Mixed gliomas are common (Zimmerman 1955; Netsky 1965) although they are diagnosed frequently as if they were pure gliomas by ignoring some components. Similarly, mesenchymal neoplasms may be mixed, as in cases of malignant lymphoma (Custer and Bernhard 1948). A unitary diagnosis, however, is often made even when multiple variants of lymphoma are present. Until recently, neoplasms of combined mesenchymal and neuroepithelial (glial) type have rarely been mentioned, and their place has not been clearly established in the classification of tumors of the nervous system. These combined neoplasms are common, but have not often been reported. Indeed. in reviewing our collections of intracranial tumors, we have frequently encountered mixed mesenchymal and neuroepithelial types of neoplasms originally diagnosed as if they were composed only of derivatives of a single component of mesenchyme or of neuroglia. The mixed mesenchymal and neuroepithelial nature in many instances, furthermore, has been obscured by such names as "monstrocellular sarcoma" (Ztilch 1961, 1965) or "giant-celled glioblastoma" (Russell and Rubinstein 1963). One case of this type of combined tumor of the brain was recently described (Shuangshoti and Netsky 1971) ; 4 more cases are now reported, and the relationship between meningioma and neurilemmoma is considered in detail. MATERIALS AND METHODS

The tissues were fixed in 10~.o formalin and embedded in paraffin. The following stains were used: hematoxylin and eosin (HE), Mallory's phosphotungstic acid hematoxylin (PTAH), Wilder's method for reticulin fibers, periodic acid Schiff (PAS), and Masson's trichrome. * U.S.P.H.S. International Postdoctoral Research Fellow ( I FO5 TW O 1528).

,I. ncuro[. Sci., 1971, 14:277 291

278

S. SHUANGSHOTI. M, G, NETSKY, J. A. JANE

Fig. 1. (Case l). intertwined bundles of the spindle-shaped tumor cells with palisades of nuclei are demonstrated. A Verocay body is located toward the left margin of the photomicrograph. HE. ~ t 10. Fig. 2 (Case 1). Syncytial mcninu~,~\tc~ ,ttL' l.'hp,tcrcd v, lthin the tumor, t i E . . , 110. Fig. 3 {Case 1). A spider-web cell, m a n x round cells with strongly acidophilic cytoplasm, and spindleshaped cells are distributed randomly. HE, ,~ 720. Fig. 4 (Case 1). A few giant cells and mesenchymal cells are shown. HE, , I II~ Fig. 5 (Case 11. A hyalinized cluster of meningocytes resembling an incompletely formed p s a m m o m a body is surrounded by many spindle-shaped t u m o r cells. HE, × 235, d. actu+oL & , . . ['~:t. 1 4 :"77 '"If

NEOPLASMS OF MIXED MESENCHYMAL AND NEUROEPITHELIAL TYPE

279

REPORT OF CASES Case 1 (U. Va. No. 625750)

A 23-year-old white man had constant headache for 1 year, and was treated for sinusitis without benefit. At the time of hospitalization, he had equivocal weakness of the right side of the tongue, and papilledema. Pneumoencephalographic and bilateral carotid angiographic findings were compatible with a mass, approximately 6 cm in diameter, lying in the posterior cranial fossa and displacing the right posterior cerebral artery, brain stem and diencephalon to the left. A right occipital craniotomy 1 week later revealed a demarcated neoplasm in the posterior cranial fossa, bspecially on the right ; it lay over the dorsum of the cerebellar hemispheres. The rostral parts of the mass extended into the right middle cranial fossa. The tumor invaded the medial surface of the right occipital lobe, tentorium, right lateral dural sinus, occipital bone and scalp. Part of the mass was removed. The patient was discharged on the 19th hospital day, but returned 3 weeks later because of continuous severe headache. A second craniotomy disclosed a cyst filled with about 40 ml of straw-colored fluid in the remaining tumor. The contents of the cyst and a large part of the mass were removed. His condition was unsatisfactory, and he received large amounts of steroids. A course of radiotherapy of 3500 r was then given with satisfactory response. The patient is living at the time of this report, 5 months after craniotomy. Both surgical specimens consisted of fragments of grey', partly rubbery' and partly hemorrhagic tissue. Microscopically, there were cells of the following types : spindle-shaped with ovoid or rod-shaped nucle~ consistent with either Schwannian cells or fibrohlasts (Fig. 1}; plump, syncytial with ovoid nuclei, considered to be meningocytes (Fig. 2); round with strongly acidophilic, either coarsely granular or homogeneous cytoplasm compatible with rhabdomyoblasts (Fig. 3); round and large with peripherally-oriented cytoplasmic vacuoles interpreted as spider-web cells (Fig. 3) ; giant cells with single or multiple nuclei, and w~th either homogeneous or coarsely-granular cytoplasm (Fig. 4); elongated cells in the form of straps or ribbons with single or a few nuclei, and occasional branches. Mesenchymal cells (Fig. 4), necrotic loci, and bundles of fibers of connective tissue were also present. The spindle-shaped cells were often arranged in streams or intertwined bundles and occasionally in loose meshes or balls, the so-called Verocay bodies (Fig. 1): the nuclei infrequently were oriented in palisades (Fig. 1). The less numerous meningocytes (Fig. 2) were usually arranged in sheets. A few clusters were much hyalinized, resembling incompletely-formed psammoma bodies (Fig. 5) surrounded by the spindle-shaped cells. The latter formed some concentric whorls with clusters of meningocytes as the central core (Fig. 6}. The round, spider-web (Fig. 3) and giant cells (Fig. 4) were scattered at random. Some elongated and giant cells contained longitudinal and suggestive cross-striations: they frequently had homogeneous. acidophilic, intranuclear inclusion bodies or vacuoles. Many normal and abnormal mitotic figures were found. Occasional groups of pyramidal cells with blue processes were seen in PTAH preparations; they were considered to be astrocytes (Fig. 7). Tumor cells infrequently adhered to or surrounded the numerous blood xessels which were angiomatous in some places. Endothelial hyperplasia was mild. Moderate numbers of reticulin fibers were disseminated among many neoplastic cells and blood vessels, but were less numerou~ or lacking in areas of necrosis, or within the groups of meningocytes and astrocytes. The surrounding cerebral tissue had undergone considerable astrocytosis. The anatomic diagnosis was mixed mesenchymal and neuroepithelial tumor (dedifferentiated neurilemmoma, meningioma and rhabdomyosarcoma combined with moderately differentiated astrocytoma). posterior cranial fossa. Comment. This case was previously considered as a Schwannian sarcoma. The gliomatous portion ~s small, Parallel rows or intertwined bundles of spindle-shaped cells with infrequent cellular palisades, reticulin fibers, angiomatous stroma, and Verocay bodies support the diagnosis of neurilemmoma. Dural attachment of the tumor, meningocytes, cellular whorls, and a few incompletely formed psammoma bodies, however, are the combined findings diagnostic of meningioma. In addition, spider-web cells, round cells with "'myogenic" cytoplasm, elongated cells in the form of straps and ribbons, and cells with suggestive cross-striations are characteristic of embryonal rhabdomyosarcoma (Stout 1946; Stobbe and Dargeon 1950). Mingled bizarre astrocytes deep within the tumor as well as vascular endothelial hyperplasia, furthermore, indicate that part of the neoplasm is an astrocytoma. Case 2 (U. l"a. No. 582887)

At l 1 years of age, this white girl first experienced a generalized seizure, and later had intermittent convulsions. At the age of 13.5 years, she suffered numbness and twitching of the face and upper extremity on the left side, bilaterally decreased vision, and frequent headaches. Six months later, she was first hospitalized with dilated and fixed pupils, bilateral papilledema and left hemiparesis. Brain scan revealed a mass

J. neurol. St'L. 19"71. 14:27"7 291

280

S. SHUANGSHOTI. M. G, NETSKY. J. A. JANE

Fig. 6 (Case 1). A cellular whorl with central meningocytic cluster is encircled by spindle-shaped neoplastic ccll~ and multiple ~malI blood vessels. Ill:. . 235, Fig. 7 (Case II, Area of astrocytoma, >howing multiple plmnp astrocyteb; note homogeneous cytoplasm. eccentric nuclei and processes. R o u n d tumor cells are also present. HE. ~ 250.

in the right ffonto-parietal region. At craniotomy, the well-demarcated tumor invaded grc~ and whne matter inferiorly and was thought to be entirely removed. At the time of discharge from the hospital, thc patient was improved, but was amaurotic because of secondary atrophy of the optic discs. Radiotherapy was not given. The specimen of firm, multilobular tumor, 6.5 cm in greatest dimension, contained interlacing bands of grey tissue on the cut surface. Microscopically, there were numerous spindle-shaped, and occasional polygonal or round neoplastic cells. The former were largely arranged in parallel or intertwined bundles Fig. 8), interspersed by sclerotic fibers of connective tissue. There were a few p s a m m o m a bodies, calcific plaques (Fig. 9) and cellular "'balls". Nuclear palisades were not seen. The polygonal or round tumor cells, considered to be poorly-differentiated ependymal cells, were arranged in the following patterns: in clusters, adherent to the vascular adventitia (Fig, 10), in suggestive papillae, or else, they were scattered at random. A few rosettes, not around blood vessels, and typical mitotic figures were noted. The widely-distributed reticulin fibers were minimal in the areas of ependymal cells. The edge of the tumor was surrounded b~ hyperplastic astrocytes, Two years after craniotomy, the symptoms reappeared and a recurrent demarcated tumor, 4 cm m greatest dimension, was again removed, and radiotherapy instituted She was living at the tlmc of this report, 6 m o n t h s after the second craniotomy. Microscopically, the now predominant ependymal cells were arranged in papillae around blood vessels (Fig. 11), in clusters, or in sheets with occasional true rosettes (Fig. 12). Mitotic figures were more numerous than previously. Some blood vessels had stratified endothelium (Fig, 13). Reticulin fibers (Fig. 141 were sparse or absent a m o n g these ependymal cells. The less n u m e r o u s spindle-shaped cells were dispersed randomly within bands of sclerotic connective tissue. The latter also contained clusters of ependymal cells, and occasional pyramidal-shaped cells having eccentric and vesicular nuclei surrounded by ample and glassy cytoplasm. These cells had occasional coarse blue processes in PTAH preparations and they were interpreted as astrocytes. .I m'ltrol, ,'~'~'I L');I 14:277 2t)l

.'r4

~ , .- .

~

,,~ ~,,,,~'~. , ~ . ~ - ¢ , ~

.,,,.

-, ~

~i~l'~,"

•

1 Fig. 8 (Case 2). Numerous spindle-shaped cells are arranged in bundles. A few round tumor cells are also scattered in the tumor• HE, x 240. Fig. 9 (Case 2). One p s a m m o m a body and a few calcific plaques are shown. HE, × b25. Fig. 10 {Case 2). Abundant round tumor cells considered to be poorly differentiated ependymal cells are attached to the vascular adventitia. PTAH, >, 240. Fig. I I (Case 2). A papilla of tumor consists of a central small blood vessel surrounded by neoplastic ependymal cells. Some of the latter have fine processes attached to the adventitia. HE, -, 235. Fig. 12 {Case 2). True rosettes of neoplastic ependymal cells with central canals are illustrated. HE, ,< 585. Fig. 13 {Case 2). A small blood vessel with prohferated endothelial cells is attached to and surrounded by many poorly differentiated ependymal cells• HE, x 235. Fig. 14 {Case 2). A fev~ reticulin fibers are dispersed through the tumor, especially in relation to blood vessels. Wilder's stare, × 235.

J. nettr~/. Nci.. 1971, 14:277 291

282

S. SHUANGSHOTI, M. G. NETSKY, J. A. JANE

The anatomic diagnosis was mixed mesenchymal and neuroepithelial tumor (dedifferentiated meningioma, and poorly differentiated ependymoma and astrocytoma), fronto-parietal region, righl. Comment. This case previously had been diagnosed as "primary malignant mesodermal tumor.'" The revised partial diagnosis of dedifferentiated meningioma is based on the following findings: spindleshaped cells, psammoma bodies, calcific loci, and reticulin fibers. We consider the term "'dedifferentiated meningioma" as analogous to meningeal sarcoma, meningioma with sarcomatous component, malignant meningioma or fibrosarcoma of the meninges (Shuangshoti, ttongsaprabhas and Netsky 1L)70) The presence of papillae and true rosettes of neoplastic cells, and bizarre astrocytes within the mass justifies the additional diagnoses of ependymoma and astrocytoma. Hyperplasia of the vascular endothelium, and the absence of reticulin fibers among these tumor cells are further evidence that the neoplasm is in part gliomatous. This case illustrates the potential significance of the lesser constituent of neoplasms with a mixed cellular population, often neglected in making the diagnosis. Ependymoma was only a small portion of the tumor at the first craniotomy, but became the prominent part in the recurrence Case 3 (Monte/iore Hosp. No. A-12,211 :

Six weeks before admission, this 57-year-old white woman suffered amebic colitis. Four weeks later. she had headaches, visual difficulty and vomiting. On admission, there were bilateral papilledema, stupor, and generally decreased motor power and tendon reflexes. The blood contained 14,800 WBC,,mm 3 with 79°,o neutrophils. The cerebrospinal fluid was normal. A mass in the left frontal lobe was detected in ventriculograms. Craniotomy in this region revealed a cavity lined by soft, grey material. A drain was inserted because of lhe impression of an amebic abscess : biopsy disclosed only cerebral tissue. A course of emetine was given, and the patient was discharged improved after 1 month. She returned 3 weeks later because of headaches, blurred vision in the left eye, diplopia and bilateral papilledema. A demarcated tumor weighing 61 g was removed from the region of the left olfactory groove and the sphenoidal ridge in a second more extensive craniotomy. The knobbly and partly cystic mass had whorling, grey cut surfaces interspersed by soft, yellow loci in the solid portion. Microscopically, the severely necrotic tumor contained multiple types of cells, most of which were elongated. One type of elongated cell had homogeneous cytoplasm and several coarse blue processes in PTAH preparations (Fig. 15). This cell was interpreted as a compressed astrocyte. Another type of elongated cell was largely spindle-shaped without blue processes in PTAH preparations, considered as a fibroblast (Fig. 16). Both types of elongated cells were arranged in streams, intertwined bundles, cellular "balls", or were frequently adherent to the vascular adventitia, especially the fibroblasts (Fig. 16). Loose meshes of mesenchymal cells were also present. Mitotic figures were numerous and were frequently atypical. Some of many widely-distributed blood vessels had severe endothelial hyperplasia. Tumor cells were often arranged in palisades around necrotic loci (Fig. 17). Reticulin fibers were generally abundant (Fig. IX}, but were sparse in areas of necrosis and where astrocytes predominated. The patient died 6 months later. Necropsy failed to disclose neoplasm outside the neuraxls. [ he swollen brain weighed 1300 g. A firm, demarcated tumor, 5 cm in greatest dimension, occupied the base of the frontal lobes, invaded the ethmoidal air sinuses, and was adherent to the dura lining the anterior cranial fossa, especially on the right. Coronal sections of the brain revealed infiltration of the tumor also into the frontal lobes, especially on the left side (Fig. 19) ; this intracerebral portion protruded into the left ventricle. and invaded the rostral parts of the corpus callosum, as well as the anterior half of the basal ganglia bilaterally. The fleshy cut surface was variegated in appearance. Microscopically, the cerebral tumor had the features previously described, but fibroblasts predominated. The tumor invaded the cerebral leptomeninges and dura mater, and had metastasized to the spinal arachhold. The anatomic diagnosis was mixed mesenchymal and neuroepithelial tumor (dedifferentiated meningioma combined with gtioblastoma multiforme}, bilateral in frontal lobes and basal ganglia, and extension across corpus callosum. Comment. This case was illustrated by Lapreste, Netsky and Zimmerman (1952) in Figs. 26 and 27 of their paper as meningioma with sarcomatous component, and by Zimmerman, Netsky and Davidoff 0956) in Fig. 89 of their atlas, as meningeal sarcoma. The initial diagnosis was based on the circumscribed outline of the mass with whorled cut surfaces, dural attachment, numerous spindle-shaped cells arranged in parallel rows, and abundant reticulin fibers in the tumor. To this diagnosis, we add glioblastoma multiforme. The presence of multicolored cut surfaces, astrocytes, loci of necrosis surrounded by palisading neoplastic cells, and endothelial proliferation are the features diagnostic of glioblastoma multiforme. Case 4 (Monte/iore Hosp. No. 48162) Eight months before hospitalization, this 40-year-old white woman became progresszvely confused, .1. neurol. So., 1971. 14:277 291

NEOPLASMS OF MIXED MESEN('HYMAL AND NEUR(-)EPITHELIAL TYPE

283

Fig. 15 (Case 31. Elongated astrocytes (spongioblasts) have fibrillary processes. PTAH, 3~250. Fig. 16 (Case 3). N u m e r o u s fibroblasts are adherent to the adventitia of a tangentially-cut blood vessel. HE, ×110. Fig. 17 (Case 31. Foci of necrosis are surrounded by palisades of neoplastic cells. HE, × 110. Fig. 18 (Case 3). A b u n d a n t reticulin fibers are dispersed in the tumor. Wilder's stain, × 110.

J. m'urol. Sci. I971, 14:277 291

284

S. SHUANGSHOTI, M. G. NE'ISKY, J. A. JANL:

Fig. 19 (Case 3). Coronal section of the brain. Intracerebral portion of the tumor occupies the base of the frontal lobes and both basal ganglia, invading the corpus callosum, and protruding into the lateral ventricles.

Fig. 20 (Case 4). Intertwined bundles of elongated astrocytes (spongioblasts) are dcinonstrated. Many tumor cells have fibrillary processes. PTAH, × 235. Fig. 21 (Case 4). Palisades of the nuclei of the spindle-shaped cells are illustrated. HE.

235.

J. neurol. Sci., 197~, J4:277 291

NEOPLASMS OF MIXED MESENCHYMAL AND NEUROEPITHEI,IAI. TYPE

285

Fig. 22 (Case 4). An area of oligodendroglioma is shown: note distinctively clear cytoplasm of the oligodendroglia. A tumor cell in mitosis is also present. PTAH, x 585. Fig. 23 (Case 4). Loose mesh of mesenchymal cells lies within the tumor. HE, × 240.

changed in personality, and had frequent incontinence of urine. She was aphasic on admission ; the blood pressure was 112,'80 m m Hg. There were hemiparesis, hyperactive tendon reflexes, and a Babinski sign, all on the right. A pneumoencephalogram gave evidence of a left frontal mass. Craniotomy revealed a firm tumor in the frontal lobe about 2 cm below the cortical surface. The neoplasm extended underneath the falx, but was not attached to the dura nor did it invade the lateral ventricle. The completely removed tumor weighed 105 g. The patient survived without neurologic deficits. Brain scan 25 years after craniotomy was normal. She then had a blood pressure of 220/110 m m Hg. and was still living at the time of this report, 27 years after craniotomy. Microscoplcall,~. there were plump syncytial cells interpreted as meningocytes, spindle-shaped cells (Figs. 20, 21) with and without polar processes, pyramidal-shaped cells with processes extending from the angular margins, round tumor cells with clear cytoplasm considered to be oligodendroglia (Fig. 22), and mesenchymal ceils (Fig. 23). The spindle-shaped (Fig. 20) and pyramidal-sh-lpcd cells with blue processes m PTAH preparations were interpreted as astrocytes; those spindle-shaped cells without processes were considered to be flbroblasts or Schwannian cells (Fig. 21 ). The latter were occasionally arranged in palisades. The spindle-shaped cells and elongated astrocytes were often arranged in streams or interlacing bundles, Mitotic figures (Fig. 22) were rare. Abundant collagenous fibers were dispersed throughout the mass. The blood vessels had normal endothelium and were moderate in number. The anatomic diagnosis was mixed mesenchymal and neuroepithelial tumor {meningioma and neurilemm o m a combined with well-differentiated astrocytoma and oligodendroglioma), frontal lobe, left. Comment. Previously,, this case was considered to be a central neurilemmoma. The features supporting the original diagnosis included nuclear palisading and streams of spindle-shaped cells. The presence of meningocytes, astrocytes and oligodendroglia, however, indicated the mixed nature of this tumor. Ziilch ( 1961 ) maintained that cells with honey-combed cytoplasm are unique for neurilemmoma, and warned that they may be confused with oligodendroglia. We are also aware that these honey-combed cells may be foamy macrophages. The clear cytoplasm of oligodendroglia, however, is distinctive. Astrocytoma and oligodendroglioma often occur together in the same mass, but they are commonly diagnosed as if they were pure, on the basis of the prevalent cell type.

J. neur~l. Sci.. 1971, 14:277 291

2~6

S, SHUANGSHOTI, M. G. NETSKY, J. A. JANF

t)ISCUSSION

General considerations It is reasonable to assume that the 4 tumors described here arose primarily within the brain. All patients had only cerebral symptoms, ranging from 8 months (Case 3) to 4 years (Case 2). In Case 3, this assumption is confirmed by the necropsy findings. In Case 4, the symptoms disappeared and did not recur up to 27 years after removal of a mass in the frontal lobe. Physical and roentgenologic examinations, including the chest, failed to disclose evidence of primary neoplasm outside the neuraxis. The histologic appearance of all 4 tumors, in addition, indicates their intracranial origin, except the rhabdomyosarcomatous part of Case 1. Rhabdomyosarcoma, however, can arise primarily in the neuraxis (Shuangshoti, Piyaratan and Viriyapanich 1968). A diagnosis based on a single cell of origin does not describe all constituents of these combined neoplasms, and, therefore is incomplete. One difficulty is that spindleshaped cells in HE preparations may be interpreted as either fibroblasts or -spongioblasts." In our view, the latter are astrocytes compressed by growing in small tissue spaces. Cases 3 and 4 illustrate this effect. The distinction can be made in PTAH preparations where the blue processes of the neuroglial cells may be recognized. Cajal's gold sublimate impregnation may presumably help to make this distinction, and with recent modifications, can be applied to paraffin sections (Folliss and Netsky 1969). Unfortunately, this technic, although it works well in the impregnation of normal astrocytes, is usually of little value with neoplastic cells. Russell and Rubinstein (1963) consider blepharoplasts as a diagnostic hallmark of ependymoma despite the recognition that blepharoplasts are difficult to identify. Blepharoplasts were not seen in the tumor of Case 2, but we consider that the diagnosis of ependymoma is correct, based on the presence of papillae and rosettes of tumor cells. We do not regard blepharoplasts, even when present, as diagnostic of ependymoma, because they may occur in ciliated cells, other than ependymal. Cilia have been identified in epithelium of the choroid plexus (Shuangshoti and Netsky 1966), in neurons and astrocytes (Del Cerro and Snider 1957: Daht 1963), in fibroblasts (Wheatley 1969), smooth muscle cells (Sorokin 1962) and in cells of meningioma (Cervos-Navarro and Vazquez 1966). Papillary patterns are said to occur in a few meningiomas (Cushing and Eisenhardt 1938; Russell 1950), but we are not certain that these tumors are pure : the possibility of combined meningioma and ependymoma as in Case 2 should be considered. Components of mixed mesenchymal and neuroglial tumors may be multiple, but ependymoma (Case 2) and oligodendroglioma (Case 4) as constituents of the neur~epithelial part are rare (Gass and Van Wagenen 1950: Siqueira and Bucy 19~,(~). Some mixed tumors are reported as if they were either pure neuroglial, or, mesenchymal neoplasms. For example, a parieto-occipital, firm, demarcated tumor was diagnosed microscopically by Hawn and Ingraham (1945) as a glioblastoma multiforme masked by hyperplasia of blood vessels. We, however, suggest that it was a combined glioblastoma multiforme and dedifferentiated meningioma, similar to Case 3. An intracranial meningioma reported by Abbott and Courville (1942) was also most likely to be a combined meningioma and glioblastoma. The pleomorphic neoplasm had ./. t~el#~',~],~ci. 19-I [4. 277 291

NEOPLASMS OF MIXED MESENCHYMAL AND NEUROEP1THELIAL TYPE

287

numerous reticulin fbers and psammoma bodies, features diagnostic of meningioma ; foci of necrosis surrounded by palisading neoplastic cells, and invasion of the corpus callosum were findings indicative of glioblastoma multiforme. Approximately 13 cases of primary rhabdomyosarcoma of the neuraxis have been reported up to the present time (Shuangshoti and Netsky 1971), including Case I. In 7 instances, the rhabdomyosarcoma was a part of a mixed mesenchymal and neuroepithelial tumor (Marinesco and Goldstein 1933; Bofin and Ebels 1963; Russell and Rubinstein 1963 : Goldman 1969; Misugi and Liss 1970, Shuangshoti and Netsky 1971),including Case 1; in some cases, the tumor was diagnosed as "'medullomyoblastoma." Recently, Misugi and Liss (1970) investigated a "medullomyoblastoma" electron-microscopically, and found neuroblastic and glial elements, myoblasts and striated muscle fibers. They suggested that the "'medullomyoblastoma" be considered as teratoid. In our view, "medullomyoblastoma" is properly classified as a neoplasm of mixed mesenchymal and neuroepithelial type. In this tumor, the only tissue foreign to the brain is striated muscle, hence "medullomyoblastoma" is not a teratoma or teratoid neoplasm. The finding of combined mesenchymal and neuroepithelial constituents in some cases (Misugi and Liss 1970) does not indicate that all reported primary rhabdomyosarcomas of the neuraxis are mixed. The tissue of origin of mesenchymal tumors arising in the neuraxis, and the mode of occurrence of combined neoplasms of mesenchymal and neuroglial type have been discussed by Shuangshoti and Netsky (1971).

Relation between meningioma and neurilemmoma The overlapping features between meningioma and neurilemmoma are seen clearly in Cases 1 and 4, indicative of an intimate relation between the tumors. A striking similarity has been noted between cells of meningocytic meningioma and of the cap cells of the Pacchionian granulation (arachnoidal villus) (Cushing and Eisenhardt 1938), leading to the proposal that meningiomas arise from the cap cells named meningocytes (meningothelial or arachnoidal cells). Occasional meningiomas, however, are composed only of spindle-shaped cells resembling fibroblasts. Some workers, therefore, propose a dual origin: meningocytic meningioma is a tumor of meningocytes, but the fibroblastic tumor arises from the fibrous constituent of the Pacchionian granulation or leptomeninges (Bailey 1940; Foot 1940), Penfield (1927) regarded fibroblasts as the cells of origin of meningiomas. Some authors gave evidence that the leptomeninges, including meningocytes, are ectodermal in origin (Harvey and Burr 1926), suggesting that meningocytes and fibroblasts are not related embryologically. Our study of the developing human choroid plexus (Shuangshoti and Netsky 1966), however, revealed that meningocytes and fibroblasts are derivatives of mesenchyme. We consider the meningocytes as modified fibroblasts, and suggest that meningioma can arise directly from mesenchymal cells as well as from meningocytes and fibroblasts. The term mesenchyme is used here to mean a type of connective tissue consisting of stellate-shaped cells embedded in a gelatinous matrix containing reticulin fibers (Walter and Israel 1965). These mesenchymal cells are pluripotential, and may .I. neurol. Sci.. 1971, 14:277 291

288

S. SH1.JAN(3SHOTI, M. G . N E T S K Y . J. A. JANf{

differentiate into fibrous, mucoid, adipose, synovial, meningeal, cartilaginous, osseous, hemopoietic, vascular, muscular and reticulo-endothelial tissues (Willis 1960). This definition is not related to the embryonic germ layer of mesoderm as is often stated in medical dictionaries and textbooks of histology. Pathologically, tissues are better described by morphologic and behavioral characteristics than by inferred embryonic derivation. Concerning neurilemmoma, many investigators hold that they arise from Schwannian cells and hence are of neuro-ectodermal derivation (Harrison 1924; Masson 1932 ; Ztilch 1961). Some workers, on the other hand, assert that these tumors arise from fibroblasts ; numerous reticulin fibers in neurilemmoma are in favor of an origin from a mesenchymal type of cell (Penfield 1927: Tarlov 1940). Electron-microscopically, Raimondi and Beckman (1967) demonstrated intracytoplasmic filaments in the cells of neurilemmoma, an ultrastructural finding in both normal (Goldberg and Green 1964) and abnormal (Ross and Benditt 1961) fibroblasts. These filaments have also been found in cells of meningioma (Raimondi, Mullah and Evans 1962) and fibrosarcoma (Hizawa and Wechsler 1966). The Schwannian cell normally wraps around the axon to form the myelin sheath. It is. therefore, to be expected that the neoplastic Schwannian cell possesses a spiral plasma membrane, but such a structure is lacking in the cells of neurilemmoma (Raimondi and Beckman 1967). These authors, in addition, found phagocytic activity in the cells of neurilemmoma, a feature not observed in Schwannian cells m rice,. They, therefore, concluded that the neurilcmmoma arose from the fibroblast. Studies of neurilemmoma in tissue culture (Murray and Stout 1940: lmmsden 1963~ and by the use of the electron microscope (Luse 1960: Pineda 1965: Cravioto 1969) have yielded findings to support an origin from Schwannian cells, and suggested that the latter can produce reticulin fibers (Nathaniel and Pease 1963: Thomas 1964). In addition, basal laminae around the tumor cells of neurilemmoma are evidence in favor of Schwannian origin (Cravioto 1969). Fibroblasts have not been found to be surrounded by basal laminae, but endothelial cells, derivatives of mesenchyme, possess this structure. Intracytoplasmic filaments are also present m reactive Schwannian cells (Bluemcke and Niedorf 1966) and in neurogtia (Terry 1963). Lumsden (1963), furthermore, observed phagocytic activity of Schwannian cells i~ l'itro. Although it is uncertain whether fibroblasts and Schwannian cells are the same type of cells, both produce reticulin fibers. We, therefore, consider that Schwannian cells are mesenchymal, as are fibroblasts and meningocytes. According to Ziilch (1961), lipid degeneration is unique for neurilemmoma, considered by him to be a neuro-ectodermal tumor; he has not observed this finding in "mesodermal" neoplasms. We and many other workers, however, have found fatty degeneration in meningiomas (Russell 1950), tumors which Ziilch (1961, 1965) classifies as "mesodermal" in origin. Ztilch (1961) casts doubt on the significance of reticulin fibers as indicative of the mesenchymal character of the neurilemmoma but he used the same finding to support the diagnosis of "'monstrocellular sarcoma". Based on these various points of view, we conclude that meningioma and neurilemmoma are mesenchymal types of neoplasms. The presence of mesenchymal cells in the tumors of Cases 1 and 4 further supports the mesenchymal nature of the neoplasms. .I m,~lr~,l

S~..

i ~) i. 14' 277 2')1

NEOPLASMS OF MIXEI) MESENCHYMAL AND NEUROEPITHEI.IAL TYPE

289

This concept explains the mode of occurrence of meningiomas in locations where meningocytes are normally absent, such as the scalp (Bain and Stinitka 1956) and in the brachial plexus (Harkin and Reed 1968) without bony attachment. It has been suggested that these extracalvarial meningiomas arise from arachnoidal cell rests (Hoye, Hoar and Murray 1960) or Schwannian cells (Bain and Shnitka 1956). Some neurilemmomas also have occurred within the cerebrum (Gibson, Hendrick and Cohen 1966) in the substance of the spinal cord without apparent connection to the nerve root (Riggs and Clary 1957), and in the eye-ball (Stallard 1938). Riggs and Clary (1957) suggested the origin of the intramedullary neurilemmoma from Schwannian cells of the peripheral nerves supplying blood vessels. Once it is recognized that meningocytes, fibroblasts and Schwannian cells are derivatives of mesenchymal cells, the origin of these unusually-located meningiomas and neurilemmomas becomes clear. According to Copenhaver (1964), mesenchymal cells line the perivascular spaces of the neuraxis. It is likely that meningioma and neurilemmoma embedded in the brain (Gibson et al. 1966) as in Case 4, or in the substance of the spinal cord, arise from these mesenchymal cells.

ACKNOWLEDGEMENTS

Dr. H. M. Zimmerman gave permission to report Cases 3 and 4. Dr. S. W. Gross supplied the clinical information in Case 4. Miss Anne Russell prepared the photomicrographs.

SUMMARY

Four cases are described of intracranial neoplasms of mixed mesenchymal and neuroepithelial (glial) type. The multipotential mesenchyme differentiated into meningioma, neurilemmoma and rhabdomyosarcoma in various combinations, but meningioma was common to all 4 instances. The neuroepithelial part was astrocytoma in 3 cases and glioblastoma in 1, but ependymoma was mingled in 1 instance, and oligodendroglioma in another. A unitary diagnosis had been made previously in each case, usually by ignoring the gliomatous component. Meningocytes, fibroblasts and Schwannian cells are categorized as mesenchymal: meningioma and neurilemmoma are interpreted as related mesenchymal neoplasms having some histologic differences. These tumors may arise directly from mesenchymal cells. This concept resolves the controversy about their cell of origin, explains their occurrence in various locations within as well as outside the neuraxis, and provides an explanation for the presence of aberrant tissues such as striated muscle in the central nervous system. REFERENCES Am~m-r, K. H. AND C, B. C~OURVILLE(1942) lntraventricular meningiomas Review of the literature and report of two cases, Bull. Los Angeles neurol. Sot., 7:12 28. B,mLk'~', O. T. (1940) Histologic sequences in the meningioma, with a consideration of the nature of hypcrostosis cranil. Arch. Path., 30:42 69.

.I. m'urol. Sci., 197l, 14:277 291

")90

S. SHUANGSHOTI, M. G. NETSKY, J. A. JANF

BAIN, G. O. AND T. K. SHNEFKA (1956j C u t a n e o u s meningioma { p s a m m o m a ) - - R e p o r t of a case, Arch. Derm., 74: 590-594. BLUEMCKE, S. AND H. R. N IEDORE (1966) Electron microscope studies of Schwann cells during the Wallerian degeneration with special reference to the cytoplasmic filaments, Acta neuropath. (Berl, ~, 6 : 4 6 6(/. BOEIN. P. J. AND E. EBELS (1963} A case of medullomyoblastoma, Aeta neuropath. /Berl. ~. 2 : 3 0 9 31 l. ('ERV(IS-NAVARRO. J. AND J. VAZQUEZ (1966) Elektronenmikroskopische Untersuchungetl i~ber das Vork o m m c n yon ('ilien in Menmgeomen, I'irchow',~ Arch. palh, Aml! , 341 • 280 290. Cop! NHAVER, W, M {1964) Bade.v', "Fe.vtt~o,,k ofHivtoloov, 15th edition. Williams and Wilkm>, Bahimore. Md.. p. 242. CRAVIOTO, H. (1969) The ultrastructure of acoustic nerve tumors, Acta neuropath. (Berl. ,. 12: II 6 t40, CUSHING, H. AND L. EISENHARD'I (1938) Meningiomas. Their Cluss([icution, Re qional Behatqour, Lift' Histoo', and Surgical End Results, T h o m a s , Springfield, Ill. CUSl"ER, R. P. aND W. G. BERNHARD (1948) The interrelationship of Hodgkin's disease and other lymphatic tumors. Amer. J. med. Sci., 216:625 642. DAttL, H. A. (1963) Fine structure of cilia in rat cerebral cortex, Z. ZellJbrsch., 6 0 : 3 6 9 386, DEL CERRO,M. P. AND R. S. SNIDER (1957) Cilia in the cerebellum of immature and adult rats, J. Miero.w., 6: 515-518. DEk CERRO, M. AND R. S. SNIDER (1969j The Purkinje cell cilium, Anal. Rec., 165:127 14tP. FOLHSS, A. G. H. AND M. G. NETSK'~"(t 969) Astrocytes in formalin-fixed paraffin sections. A new modification of Cajal's technic and comparison with the hematoxylin and eosin method, Amer, ,L clin. Path., 39: 416-419. Foot, N. C. (1940) Meningioma, Arch. Path., 30:198--211. GASS, U. AND W. P. VAN WAGENEN (1950) Meningioma and oligodendroglioma adjacem m the brain, J. Neurosuro. , 7: 440-443. GIBSON, A. A. M., E. B~' HENDRICK aND P. E. (,'ONEN (1966) lntracerebral Schwannoma. Report of a case. J. Neurosurq., 24:552 557. GOLDBERG, B. AND H. GREEN (1964) An analysis of collagen secretion by established mouse fibrobtast lines, J. Cell Biol., 22: 227--258. GOLDMAN, L. R. (1969) Oliomyosarcoma of the cerebellum.Report of a unique case, Amcr, J. elin. Path., 52:741 744. HARK1N. J. C. AND R. J. REED (1968) Atlas of Tumor Pathology, 2nd Series, Fast. 3 , 7)tmm'v o l t h e Per# pheral Nervous ,~vstem ;, Armed Forces Institute of Pathology, Washington, D.C.. p, I ~. HARRISON, R. (1924) Neuroblast cersus sheath cell in the development of peripheral nerves, J, comp. Neurol., 37: 123-205. HaI~VE¥, S. AND H. BURR (1926) The development of the meninges, Arch. Neurol. Psvchiat. :Chic.), 15:545 567. HAWN, C. V. Z. AND F. D. INGRAHAM (1945) Blood vessel hyperplasia masking gliobtastoma multiformc. Report of a case, J. Neuropath. exp. Neurol., 4: 364-369. HIZAWA, K. AND W. WECHSLER (1966) Zur Feinstruktur des Fibrosarkoms der Dura. Beitr. path. Anat., 134 : 449-463. H o w , S. J.. C. S. H o a r AND J. E. MURRAY (1960) Extracranial meningioma presenting as a rumor of the neck, Amer. J. Sur~l., 100: 486- 489. LAPRESLE, J., M. G. NETSK¥ AND H. M. ZIMMERMAN(1952) The pathology of meningiomas. A study of 121 cases, Amer. J. Path., 2 8 : 7 5 7 791. LU~,1SDEN, ('. E. (1963) Tissue culture in relation to tumours of the nervous system. In: D. S. RUSSEt.t, ANt) L. J. RUBINSTEIN(Eds.) Patholoqv o/Tumours qfthe Nert'ous System 2nd edition Williams and Wilkins, Baltimore, Md., pp. 31%322. LusE, S. A. (1960) Electron microscopic studies of brain tumors, Neurolooy (Minneap. :. 10: 881-905. MARINES('O, G. AND M. GOLDSTEIN (1933) Sur une forme anatomique non encore d6crite de mhdulloblastome: Mhdullo-myoblastome, Ann, Anat. path., 10: 513-525. MASSDN, P. (1932) Experimental and spontaneous Schwannomas (peripheral gliomas), Part 1 (Experimental Schwannomas), Part 2 (Spontaneous Schwannomas), Amer. J. Path., 8: 367-416. MISt GI. K. AND L. LISS (1970) Medulloblastoma with cross-striated muscle. A fine structural study. Cancer (Philad.), 25:1279 1285. MURRAY, M. R. AND A. P. S'rOUT (1940) Schwann cell versus fibroblasts as the origin of the specific nerve sheath tumors. Observations of normal nerve sheath and neurilemmomas in vitro, A mer. J. Path., 16: 4l 60. NATIIANIEL, E. J. t-l. AND D. C. PEASE (1963} Collagen and basement membrane formatmn by Schwann cells during nerve regeneration, J. UItrastruet. Res., 9: 55(~-560.

,I. n,,urol. Sci,, I~YT1, 14:277 291

NEOPLASMS OF MIXED MESENCHYMAI, AND NEUR()EPITttELIAI. TYPE

201

NETSKV, M. G. (1965) Experimental induction and transplantation of brain tumors. In: K. J. ZI~ILCHAND A. L. WOOLF (Eds.), Class!/~cation of Brain Turnours ( Acta Neurochir.,Suppl. A'), Springer, Vienna. pp. 46 56. I'ENEIEU). W. (1927) The encapsulated tumors of the nervous system. Meningeal fibroblastoma, perineurial fibroblastomata and neurofibromata of Von Recklinghausen. ,~'uro. (il'm'c. ()h.~Ict., 4 5 : 1 7 8 18S PtNkl~',, A. (1965) Collagen formation by principal cells of acoustic tumors, Neuroh~ly (Minne~q~. ;, 15. 536 547. RAIMONDI, A. J. AND F. BECKMAN (1967) Perineurial fibroblastomas. Their fine structure and biology, Aeta neuroputh. ( Berl. ), 8 : 1 23. RAIMONDL A. J., S. MULLAN AND J. P. EVANS (19621 H u m a n brain tumors. An electron microscopic study. J. Neurosurg., 19:731 753. RIGGS, H. E. AND W. U. CLARY (1957) A case of intramedullary sheath cell tumor of the spinal cord, Considerations of vascular nerves as a source of origin, J. ?@uropath. exp. Neurol., 16:332 336, Ros',. R. x x n t:. P t'h:x,l)lT'I (1961) W o u n d healing and collagen formation, Part [ (Sequential changes in components of guinea-pig skin wounds observed in the electron microscope), J, hiophys, hioehem. Cytol., 11 : 677 700. RUSSELl_, D. S. (1950) Meningeal tumours. A review, J. elin. Path., 3:191-211. RUSSELL, D. S. AND L. J. RUBINSTEIN (1963) Pathology o/" Tmnours o1" the Nervous System. 2nd editmn, Wilhams and Wilkins, Baltimore, Md., pp. 12, 132 133, 154-155. SfIUANGSHOTI, S. AND M. G. NETSKY (1966) Histogenesis of choroid plexus in man, Amer. J. Anat., 11 S: 283 315. NHII~,N(;SlIIIII, q. X.kl) M. G. NETSKY (1966)Choroid plexus and paraphysi~ in lower vertebrates, .I Morph., 120:157 lgS. SmrAN6SHOTI, S. AND M. G. NETSKY (1971) Neoplasm of mixed mesenchymal and neuroepithelial origins: An alternative interpretation of "monstrocellular sarcoma" or "'giant-celled glioblastoma", J, Neurosur:t.. 34:803 813. SHtrA',GSHOTL S., C. HONGSAPRABHASAND M. CJ. NETSKY (1970) Metastasizing memngioma, Cancer :Philad,), 26:832 841, SrqUEIRA, E. B. AND P. C. BucY (1966) C h o n d r o m a arising within a mixed glioma. J. Neuropath. exp. Neurol., 25: 667-673. SOROKIN, S. (1962) Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J, Cell Biol., 15:363 377. S LaLL,a,Rn, H. B. (1938) A case of intra-ocular neuroma (Von Recklinghausen's disease) of the left opnc nerxe head, Brit..I. Ol~hthal., 22:11 lS Sit mBF, G. D..AND H. W. DARGEON (1950) Embryonal rhabdomyosarcoma of the head and neck in chddren and adolescents, Cancer (Philad.), 3: 826-836. STOUT, A. P. (1946) R h a b d o m y o s a r c o m a of the skeletal muscle. Ann. Surg., 123:447 472. T:,RLOV, I. M. (1940) Origin of the perineural fibroblastoma, Amer. J. Path., 16: 33-40. TERRY. R. D. (1963) The fine structure of neurofibrillary tangles in Alzheimer's disease, J. Neuropath. exp. Neurol.. 12: 629-642. THOMAS, P. K. (1964) The deposition of collagen in relation to Schwann cell basement membrane during peripheral nerve regeneration, J. Cell Biol., 23:375 382. WAt. fER, J. B..~.ND M. S. ISRAEL (1965) General Patholocly, 2nd edition. Little, Brown. Boston. Mass.. p. 606. \~ III ,\1I F'~, D 'k. (I 9601 Cilia in cell-cultured fibroblasts, Part I ((In Iheir occurrence and relahve frequencies in primary cultures and established cell lines), J. Anat. (Lond. J, 105:351 362. WILHS, R. A. (1960) Pathology o f Turnours, 3rd edition, Butterworths, London, p. 646. ZIMMERMAN, H. M. (1955) The nature of gliomas as revealed by animal experimentation, Arner. J. Path., 31:1 30. Z IMMERMAN, H. M., M. G. NETSKY AND L. M. DAVIDOFF {1956) Atlas of Turnors o f the Nerrous Sj'stem, Lea and Febiger, Philadelphia, Pa., pp. 32-37. 55 63. Z¢)LCH, K. J. {I961) Neurinomas, meningiomas, and related tumors, In: W. S. F~ELDSANI) P. C. SHARKEV (Eds.), The Biolog' and Treatment of lntracranial Tumors, Thomas, Springfield, Ill., pp. 218 247. Zf'LCH. K. J. 0965) Brain Tumors. Their Biolo#y and Patholocly 2nd edition, Springer, New York. N.Y., pp. 202-214, 221-223.

J. neurol. Sei., 1971. 14:277 291