TUMORS OF THE PERIPHERAL NERVES
CHARLEB F. GESCHICKTER, M.D. 1 (From the Surgical Pathological Laboratory, Department of Surgery, Johns Hopbins Hospital and University)
The individual fiber of a peripheral nerve is composed of an axon or neurite, which is usually encased in a myelin sheath. Surrounding this is a protoplasmic envelope, the sheath of Schwann. These ele- ments, the neurite, the myelin sheath, and sheath of Schwann, are neurogenic in origin (Fig. 1). The neurite is a prolongation of an individual nerve cell, while the sheath of Schwann is composed of a syncytium of cells which migrate out from the neural crest in early embryonic life (Harrison). The myelin sheath is supposedly a product of the nerve cell. The individual nerve fibers are embedded in con- nective tissue, the endoneurium, and are gathered into bundles enclosed by fibrous tissue, the perineurium. The entire nerve, consisting of these bundles of individual fibers, is overlaid by connective tissue, re- ferred to as epineurium (Fig. 2). Tumors of the peripheral nerves were divided by Virchow, in 1863, into false neuromas, which include tumors of the nerve sheath, and true neuromas including growths arising from nerve fibers or nerve cells. Among the true neuromas are ganglioneuromas of the periph- eral, spinal, and sympathetic nerves, and amputation neuromas, which are a combination of nerve fiber and sheath regeneration following the severing of a nerve trunk. Sporadic examples of neuro-epitheliomas of the peripheral nerves have been reported. The false neuromas or tumors of the nerve sheath are far more common than tumors derived from nerve fibers. Tumors of the nerve sheath occur on both spinal and sympathetic nerves, on both sensory and motor nerves, centrally at their roots, peripherally on the deep nerve trunks, and superficially near the terminal ramifications, particu- larly in the subepidermal tissues. According to one school these tu- mors are derived from the sheath of Schwann, ie., are of neuro-ecto- dermal derivation ; another seeks their origin in the connective tissue of the endoneurium and perineurium. Clinical-anatomical classifications of nerve sheath tumors have been attempted, the best defined clinical group being the multiple variety described by von Recklinghausen. These tumors are sometimes heredi- tary and are extremely varied in their manifestations. Melanotic plaques in the epidermis, subcutaneous multiple fibrous tumors, plexi- form involvement of the nerves of an extremity with or without elephan- tiasis, and solitary nodules on the deep nerves, both benign and malig- nant, are among the varied findings. Two varieties of solitary benign nerve sheath tumors are recog- nized, a differentiated and undifferentiated group. The more highly
1 Aided by a grant from The Anna Fuller Fund. 377 378 CHARLES I?. GESCHICIZTER differentiated tumors arc rich in collagen and fibrous tissue and in one or more zones of the tumor a clumping of the nuclei in a characteristic palisade arrangement ca.n be seen iiiider the microscope. These tumors are surrounded by the perineurium except at the point of attachment to the nerve and rarely uiidcrgo malignant change. “hey have been variously termed perineural fibroblastomas, nenriiiomas, Schwannomas, neurilemomas, and lemmomas. They occur most frequently in the sub- cutaneous tissues or centrally along the root,s of the cranial or spinal nerves in adults. The tumors of the undifferentiated group may or may not be en- capsulated and are prone to recur and to undergo malignant change. These tumors occur most frequently on the deep nerve trunks of the upper or lower extremities and also superficially beneath the epidermis. Both children and adults may be affected. The combination of mul- tiple superficial and deep tumors of this type is part of the clinical picture of von Reeklinghausen’s disease. Histologically these growths are composed of reticulated myxomatous tissue often arranged in bundles and sometimes extremely cellular. These tumors have been variously referred to as fibromyxomas, fibroneuromas, and myxoicl neurinomas. Sarcoma of the nerve sheath may arise in either type of solitary nerve tumor just mentioned. It is the most common form of sarcoma of the soft parts. Usually this malignant change affects the deep nerve trunks of the extremities, and it may complicate von Recklinghausen’s disease. The following table shows the classification and the incidence of these tumors recorded in the Johns Hopkins Surgical Pathological Laboratory.
Tumors of the Nerve Sheath (False Neurotnas)...... Palisaded neurinomas (Neurilemomas) ...... Peripheral (55 cases) Spinal (25 cases) Acoustic (70 cases) Myxoid neurinomas (Neurilemoblastornas) ...... Subepidermal (240 cases) Deep (70 cases) von Recklinghausen’s, multiple (40 cases) Sarcoma ofthenerve sheath ...... 350 cases Tumors of Nerve Fibers (True Neuromas) ...... 50 cases Amputation neurom ...... 40 cases Ganglioneuronia ...... 8 cases Peripheral neuro-epitheliomas...... 2 cases Total ...... 900 cases
TUMORSOF THE NERVESHEATH: FALSE NEUROMAS Palisaded Nezwinonias (NeurilPrnornas) The palisaded neurinomas arise from the sheaths of the subcu- taneous nerves or the roots of the spinal or cranial nerves. They are encapsulated hy the pcrineurium, are solitary, and do not implicate an entire nerve trunk. With the peripheral tumors a tender lump FIQ.1. PHOTOMICROGRAPH OF A NORMAL MEDULLATEDNERVE FIBER OCCURRING IN AN AMPU- TATION NEUROMAON TIIE SCIATIC NEWE The axon courses through the center of the myelin, which stains in the form of small droplets. The nucleated sheath of Schwann is seen above the fiber. Above and below are the anastomosing columns and fibers of the Schwannian syncytium. Masson 's trichrome stain. Path. No. 56853.
FIQ.2. PHOTOMICROQRAPH SHOWING THE CONNECTIVE-TISSUE SHEATHS 0% A NORMALNEltVE Ep. Epineurium. Pe. Perineurium. En. Endoneurium. Laidlaw's silver stain. Path. No. 60885.
379 380 CHARLES P. GESCHICKTER may be palpated in the subcutaneous region, and pressure may provoke pain referred along the distribution of the affected nerve. About one- third of these tumors lie immediately beneath the epidermis (Fig. 5). Stout has reviewed the literature on the peripheral tumors of this type, collecting 194 cases and adding 50 of his own. He has suggested
FIG. 3. DISTRIBUTIONOF SUBEPIDERMAL AND CENTRAL PALISADED NEURINOMAS The location of the tumors was as follows: Peripheral tumors Head and neck, including facc, scalp, and eyelids ...... 18 Upper extremities ...... 14 Trunk ...... 12 Lower extremities ...... 6 Central tumors Acoustic nerve ...... 70 Spinal cord and cauda equiiia ...... 25 the term neurilemoma for these growths. In the central tumors involvement of the cranial nerves or compression of the spinal cord is the outstanding feature. Whether these tumors are central or peripli- era1 in distribution the upper portion of the body and the upper extremi- ties are affected more often than the lower. With the central tumors the cranial nerves are involved more frequently than the spinal roots, TUMORS OF THE PERIPHERAL NERVES 381 and in the subcutaneous regions the head and neck and upper extremi- ties more frequently than the trunk and lower extremities (Fig. 3). On the extremities the flexor surfaces are usually affected. Eighty per cent of all cases occur in adults between the ages of thirty and fifty years (Fig. 4).
FIG.4. AGE DISTRIBUTIONOF NERVESHEATH TUMORS
Histologically these are benign, well differentiated tumors showing varying degrees of fibrosis, which is maximal in the region of the capsule. A few degenerating axons with myelin sheaths may be dem- onstrated by special stains but these are persisting normal structures and not part of the new growth. The major portion of the tumor is composed of wavy bands of collagen interspersed with elongated paral- lel fibrils (Fig. 6). Whorls of fibers may occur and in these zones clumping of the nuclei to produce so-called palisades may be seen (Fig. 7A). This is referred to by Antoni as Type A tissue. Interspersed with the collagenous and palisaded structures there is a loose reticu- lated tissue containing cells with small nuclei, many fine radiating fibrils, and minute cystic spaces. These reticulated or loose-meshed areas, termed by Antoni Type B, can be found in all of these growths, but the palisading is a more helpful finding from the standpoint of diagnosis (Fig. 7B). Masson has studied in detail the cytological characteristics of the predominating cells in these tumors, which he believes are sheath of Schwann cells or lemmocytes. The nuclei are fairly large with mod- erate amounts of chromatin arranged at the periphery. The cytoplasm of the cell is abundant and forms syncytial columns of protoplasm marked by numerous delicate fibrils arranged both longitudinally and circularly. This syncytium stains pink with Masson’s trichrome stain; it is encased in a reticulum of fibers which stain blue by this same method. We have been able to confirm Masson’s findings in the present study. When a reticulum stain is used the entire tumor is seen to be 382 CHARLES F. GESCHICKTER
crowded with many fine fibrils, which Masson believes are derived from the lemmocytes of the sheath of Schwann rather than from the con- nective tissue of the endoneurium. These subcutaneous or peripheral neurilemomas may be trealed by simple excision. Sacrifice of an important nerve is not necessary, since the deep peripheral nerves are rarely involved and recurrence after excision is extremely uncommon. Malignant change has occa- sionally been reported (Stewart and Copeland; Peers) in tumors in the deeper tissues but not in those in the subcutaneous regions. Acoustic Nerve !l'unzor.s : Tumors occupying the cerebelloporitine angle and involving thc acoustic nerve comprise about 10 per cent of all
FIG. 5. PHOTOMICROQRAPH OF SUREPIDERMAL PALISADED NEURINOMA. PATH. NO. 16620
intraeranial neoplasms. In the present series 105 cases were placed in this group, on the basis of operative findings. Of this group 70 were selected as typical after microscopic study. The majority of these cases were from tlic surgical service of Dr. Walter E. Dandy, although 10 of the cases had been previously reported by Cnshing. The acoustic tnmors in the present series, with two exceptions, occurred in adults beyond the age of twenty years. The two younger patients were eighteen and nineteen years of age. The duration of symptoms is prolonged, extending beyond a five-year period in many instances. A characteristic syndrome is usually present, beginning with a roaring in the ears or dizziness, after which the hearing is gradually lost 011 the affected side. There is loss of sensation over the affected side of the face and occasionally in the anterior two-thirds of the tonguc. The voice may become thick and the patient becomes TUMORS OF TEE PERIPHERAL NERVES 383 ataxic, with a staggering gait. The symptoms relate to the eighth, fifth, seventh, and ninth cranial iierves on the affected side and to the cwebellum. They are f ollowed by signs of intracranial pressure in- cluding headache, impairment of vision, and vomiting. The findings on examination include impairment of hearing,' loss of vestibular response on caloric test (absence of nystagmus when the ear is irrigated with hot or cold water), and absence of the corneal reflex on the affected side. Facial asymmetry and anesthesia, nystag- mus, ataxia, paralysis of the vocal cords, dysphagia, and hemiatrophy of the tongue are among the other findings. Grossly these tumors are encapsulatecl and vary in color from a
FIG. 6. LOW-POWER PIIOTOMICROGRAPII OF AN ENCAPSULATED PALISADED NEURINOMAOK NEURILEMOMA.PATIT. NO. 42721 From Lewis aiid Hart: Ann. Surg. 92: 963, 1930. grayish white to a yellow or red. They are usually fibrous but may be quite vascular. They range in size from one to several ceiitimeters in diameter. At operation they are found just beneath the cerebellum, which must either be lifted or uncapped before the tumor presents. Dandy prefers a complete enucleation of the tumor with the curettc, followed by removal of the capsule, whereas Cushing is often content with intracapsular enucleation, awaiting the possibility of recurrence before more radical removal. The operative mortality is between 15 and 25 per cent. Paralysis of the facial nerve follows surgical removal of these lesions and anastomosis is usually performed at a second stage between the peripheral portion of the seventh nerve and the central portion of the eleventh.
2 In rare iiistaiiees the hearing may be retained. 384 CHARLES F. GESCEIICKTER
These tumors show varying degrees of vascularity and fibrosis. The more cellular growths resemble spongioblastomas or glioblastomas of the brain and the more fibrous lesions resemble meningiomas. In one or more portions the tumors show typical reticulated tissue and elsewhere collagenous areas with clumping of the nuclei, They do not differ as a group from the palisaded neurinomas found on the periph- eral nerves (Fig. 8). There have been various theories as to the nature and origin of these tumors. The frequency of their occurrence in the region of the cerebellopontine angle has led Sternberg, Verocay and others to refer them to embryonic rests occurring in the complex development of this
FIG.7. Two AREAS FROM THE TUMOR~IIOWN IN FIQ.6: A. TYPEA TISSUE (LEFT) SHOWING PALISADING.B. RETICIJLATED AKEA, OR TYPEB TISSUE (RIQHT) Fig, 7A from Lewis and Hart: Ann. Surg. 92: 964, 1930
region. These tumors, however, have been reported, also, on the seventh nerve by Raymond, Huet and Alquier and on the fifth nerve by Cohen and by Glaser. Cooper has reported two neurinomas in- vading the Gasserian ganglion. He was able to collect from the litera- ture records of 76 tumors affecting this structure. One of the cases in the present series involved the tenth and another the twelfth cranial nerve. A series of six tumors ranging from 1 to 3 mm. in diameter has been collected in Dr. Crowe's laboratory for otological research at the Johns IIopkins Hospital, on the distal portion of the eighth nerve within the internal auditory canal. The histology of these minute tumors on the distal portion of the nerve, is identical with that of the larger tumors at the cerebellopontine angle and of the tumors on the peripheral spinal nerves. This substantiates the origin of these tumors from the sheath of the acoustic nerve. Ex;tramedullary Neurilemomas of the Spi.na1 Cord: Tumors of the palisaded neurinomatous type occur on the spinal cord in an extra- medullary location. They may be intradural or estradural and occur on the roots of the spinal nerves within the vertebral canal anywhere TUMORS OF THE PERIPHERAL NERVES 385 from the cervical region to the cauda equina. They are sometimes multiple or associated with meningeal tumors in the presence of von Recklinghausen’s disease. The symptoms produced vary with the level of the tumor. The onset is usually insidious, indicating cord compression with unilateral sensory and motor disturbances. Root pains exacerbated by coughing or sneezing occur. Girdle pains, weak- ness of the legs, progressive paralysis (at first spastic) below the pain- ful area, and disturbance of the bladder and rectal functions, are common findings. Diagnosis is much aided by the injection, in the subarachnoid space above the lesion, of lipiodol and roentgenographic demonstration of a block in its downward course.
FIG. 8. PHOTOMICROGRAPH OF AN ACOUSTICTUMOR SHOWINQ TYPICALPALISADES. PATH. No. 41391
Tumors in the anterior portion of the cord are more difficult to locate and to excise. The tumors are usually encapsulated and do not invade the cord, but in one case in the present series associated with von Recklinghausen’s disease there was definite invasion and a portion of the tumor was left behind at the operation (Fig. 9). In other cases the growth may form an anterior extension (so-called hour-glass tu- mor), the major portion being found in the neck, mediastinum, or in the retroperitoneal spaces. Tumors of the cauda equina present certain diagnostic difficulties. The majority of tumors in this region are sheath tumors, the neuri- nomas being more common than the meningiomas. The pain, which may be very prolonged, is frequently attributed to sacro-iliac arthritis or sciatica. There is flaccid paralysis with loss of reflexes and marked disturbance of the bladder and rectal functions. An area of “ saddle ” 386 CHARLES I?. OESCHICKTER
anesthesia is present in the perineum. The exposure of these tumors at operation is more difficult than those of the spinal cord, but the prognosis is better. The distribution of these sheath tumors in the spiiid cord and in the cauda equiiia, is as follows:
Cervical region...... 6 cases Thoracic region. . :, ...... 7 cases Lumbar region ...... 2 cases Caudaequina ...... 10 cases - T~TAL...... 25 cases
B’IG. 9. PHOTOMICROQRAPH OF AN EXTKAMEDLTLLARY NEURILELEOMAOF THE SPINAL CORD CO~IIPLICATING A CASE OF VON RECKLINQIIAUSEN ’S DISEASE A portion of the tumor invaded the cord. Path. No. 53373.
Mymid Neu r.il1.o Inas or Neir ril erii ob 1ad om as The myxoid neurinomas of the nerve sheath differ €rom the pali- saded neurinomas both clinically and pathologically. The distribution of these tumors is subepidermal and along the deeper nerve trunks, in contrast to the subcutaneous and central location of the palisaded neurinomas. These myxoid tumors also have a wider age distribu- tion and occur more frequently in children. The majority of the tu- mors are not encapsulated. Histologically they are more undifferen- TUMONS Oh’ THE I’EKIl’HEI
TABLEI: Coinparifion of Palisaded and Myxoid Neurinonias
~-______-___--____ ~ -_____._ ~~ _____~-~~___~ _ ~ - ~ 1 Nrurilrmomas ! Neurilrmohlastoma~
Kumber of C:MS I 150 I 350 Age peak 40-50 20 30
~ __~-~ - ~ Children affected Sone 20 pei cent _- ______~ - ~ ~ ~- ~ _____ - Most frequent loratioti< Roots of eighth ciamal Subepidermal fibers, deep and spinal nerves, sub- nerve tiiiiiks of upper and cutaneous fibers, head lo~er extremities, visceral and neck, at m, hand syrnpathetics ______- ~~ .-__ Enciipsulation Majority encapsulated Majority not eiicapsulated ~ - __~ __ -__ -~ Mici osropic findings Palisading arid hbrous Reticulation and myxomatous tissue tissue __ ___--_ ~- __ ___ - Behavior aftei tieatment No recurrence after qim- Tendency to recur ntter sirn- ple excision ple excision Malignant change Rare Common __- ____-- ~._~______-_____~__- Association 5% ith von Rechlingliausen’s Rare ( ’ommori disease
Subcpidcrwnl JIyroitl Neririizo ~uns(No-rulletl Nmvofib ro mas) : Sub- epitlcrmal ~iodulcsnssociatrd ivitli the ~lieafh~of tlic 1)criphcral nerves are arnoiig the most Conimoii tumors. Nearly every patient examined will bc found to have one or two of these pcduiicixlated lesions several millimeters in diameter. They differ from the lcsious found in typical von Becklinghausen’s disease in the absence of symptoms produced, their small size, their rcstrictetl niimbei‘s, ant1 their failure lo follow the entire cutaneons distribution of the nerve. hi tlic present series of castis t1ici.e were 240 tumors of appreciahle size Tvhich hat1 been excised and classcd as neiirofihromas after niicr.oscopic study. These growths \vei-c usually removed for cosmetic reasons, although rarely increase in size or cleepeiiing pigmentation was the indication for excision. In some cases the nodules had become iiicreasingly painful or tender. With few cmeptiorts orily a single turnor was removed from an incli- vidnal. The notlules were more f1~cqncntlysituated on the extremities than on the Iicacl, neck or trunk (Fig. 10). Microscopic study discloses tlii*ce types of su1)epiclermal nodules associated with bhc 1ien-c shcath. The most common form is charac- tcrizecl hy an increase in adult c~oriiiectivetissue ;uid is often considered, erroneously, a simple fibroma (so-called fibi*omamolluscum). Another foi*mis composed of bundles or fasciculae of c~loiigtitetlcells wliich may 388 CHARLES Y. UESCIUCKTER
1)e arranged in whorls, some of which display marked cellularity. A third type is cornposed of a diffuse proliferation of small spindle cells vithout any characteristic arrangement. Any of these three histologic types may be associiitetl with melanin pigment (Figs. 11-13), arid none
I’IO. 10. DISTRIBU~I’IONOF KUPEHPICIAL AND DEEP MYXOIDNEUKINOMAS ( NEUIULEMOBI ASTOMAS)
of them sl.iows complete encapsillation. They represent three stages of differentiation in tlie same pathologic process. Tlie essential patho- logic change is apparently a proliferation of sheath cells about onct or more bundles of iierve fibers eiit eriiig tlic subepidermal region. Tlie nodules cornposed of undifferentiated spindle cells represent the earliei. phase of n process which tcrminntes with fibrosis after passing through ;i stage cliarncterized by bundles of eloilgated sheath cells. Multiple nodules of this character are the outstanding feature of von Recklinghauscn’s disease. Penfield as able to stain axons of nerve fibers enteriiig tlie subcutaneous nodules, and interpreted notlulcs as a, reactionary fibrosis of probable neurotrophic origin. r.ctained the term ncnrofibroma for these lesions, because of the axon TUMORS OF THE PERIPHERAL NERVES 389
found in the tumor area. From the present study no special signif- icance can be attached to the demoiisti*ation of asonal fibers in these nodulcs. They can IE demonstrated iii the normal skin and subcu- taiwoiis regions anti their pel-sistciice in the tiffectecl area is not iieces-
FIG.11. LOW-POWERAND IIIGII-POWER PHOTOMI('R0GRAPHS OF A SUBEPIDERMAL NEURILE~~OI~LASTOMA Mature cwllngcnous fillers prrclomiiiatr. Path. No. 31502.
FIGS.12 AND 13. SUBEPIDERMAL P\TEURII~EMOBLASTOIIAS The tumor in Fig. 12 (left), occurring in a child of seven months, is composed of inter- lacing bundles of collagenous fibrils (E'oot's reticulum stain). The tumor in Fig. 13 (right) is composed of undifferentiated spindlc cells; a small deposit of melanin is seen in the lower riglit Imid corner. Path. Nos. 547% and 3272!5.
sarily related to the pathologic changes (Figs. 14 and 15), but merely indicates proximity to iicural structures. In general neither axons iior myelin arc found as part of the neoplastic process in tumors of thc nerve sheath. Subepidermal Nerve Sheath Sarcoma, Grade I. : In the present series there was a group of 30 very cellular spindle-cell tumors oc- ~’IG. 14. ~1~OTOMI~’KOOKAI’IIOF A SITREPIDERhrAL NODULEOCCURRING ON THE NERVE SIIRATII A large IK~WC~fibri. is wen cntciing thc tumor. Path. No. 32414.
FIG. 15. PIlOTOhIICROORAP€€ OF AXONALmBERS ENTERINGA SUBEPIDERMAL NODULE (1~IELSClIOWSIZY’S STAIN). PATlI. NO. 54958 TUMORS OF THE PERIPHERAL NERVES 39 1
curring immediately beneath the epidermis and apparently of nerve sheath origin (Figs. 16 aiitl 17). These cases were formerly classed in the lahomtory as siircomas of thc skin. With few clsccptions they
FIG.17. ~HOrl~O~31 give the impression of being encapsulated, but they frequently extend without any ticfinite boundary above or below, up and down the nerve trunk. These tumors are usually larger at the time of their clinical rec.ognitioii tliaii the other varieties of nerve sheath tumor, varying from the size of a u7al11ut to that of a grapefruit. ‘I’hey tciitl to have a somewhat gelatinous consistency and a gray, translucent appcaraiice. Althoiigh pain and tingling along the distribution of tlie iicrvc may hc coinplairietl of by the patient, the fairly rapid growth of the swelling is often the only significant finding in the history. b’l0. 19. LOW POWER AND IIlGIf POWER I’IIOT03II(‘KOGKAPIIS OF A LfYXOlD NEURINOMA IN TllE WALL OF mI.: STO~IACH Tlici tumor is undergoing malignant cl-inngc. Path. No. 55320. The outstmclirig cliiiictil fcaturc in this groiq) of tnmors is the iendency to reciii-reiice. Thii*ty rxr ceiit of the tumors in t lie present series i*c~ciirrc~4ant1 of the iwinwiit giwwths slightly moi-c than half nnderweiit m;digiiani t (~haiige,nwiltiiig- iii the death of the patieiit. Whcrcas siml~leewisioit siiffices iii the tiwtment of the sulwpidermal nodules an(1 the pdisaded iicwi.iiiorrias, thc mysoitl iiciu.iiiomns should without c.sc.eptioii he clscisetl \\.it11 a rn;ii.giii of liedthy tissue. If a major nerve trunk mist be sac.rificct1, this should be done with an attempt at sitbsequciit iiei-ve sutui~~.These tumors in oiir ospci.icnce have not p~rvetlrdioseusitivcl. Histologically, 11ic~sogiwwths are composed of intci*lac*iiigstralitls of eloilgated or s1ioi.t spiiitlle cells with varying amonnts of collagciious and mysomatous iiiterc~e1liil;tr sn1)staiice. Reticulated arcas in which small brniichirig cells lie free in a traiisluceitt matrix arc a prominent feature. Marlied filirosis ant1 definite palisading vere iiot presciit in the sections examiiied. From the standpoint of treatmciit ally nerve 394 CHARLES F. (iESC’IIICK‘l‘ER sheath tumor occurring on the deeper nei’ve ti.iinks or on the sympa- thetic nerves of the viscera. should be r.cscctecl rather than excised on imptive cvitlcw+cthat it 1)clloilgs to this group (Figs. 20-22). I11 nmors of this typo exwediiig 2 em. it1 diameter arc usually malignant. Nr)ii.ofiOi.onintosis.- TTon Bec~ltliti~:.h;inscn’s disetisc or ncurofibromn- tosis is a coii~*~ilitaltlisturbancc of the nerve sheaths resulting in ? multiple subcpitlermal riocliilcs dong the distribution of the peripliernl ~i~~rvcs,tumors of the drepei. iiervc triiiiks an(l roots, ant1 clistur1)anecs in pigmcii tation. Mciiingcal tiimoix, angiomas, lipomas, and tropl-iic tiisturlmiccs, such as hypertrophy of a limb 01’ spiiia hifitla, are often ikssocil-ttd coiiditioiis. Typical c;~sesiii \vliich tumor nodules are widely (iistrihted over tlic Iwdy are iiot cornmoil, I)ut atypical cases (so-callctt ), iil which oiic 01’ more areas of the htly sliow pigmen- tation and tumor 110(1111cs, are see11 more f rcqueiitly. ‘l’he present study is 1,ascd npoii 40 typical cases in which tissue was available for study followiiig snrFica1 excision or autopsy. Although ci~scs111 wliic*h the cliscasc shows licrctlitury or familial features are not rare in the 1iteratui.e (Stulmann), in tlic present series of 40 c~ascsiio iiisttince is recordctl in which memhers of the patient’s family were laiown to he affcctcil. The diseuse pnrsucs a slow, insidious course, approsimatc~lyoiic-third of the I>aticntsbciiig in the third decaclc before disability or disfigurcmeiit brings them to 1lie physician. Al- though the majority of tlie ptieiits were between tlie ages of twenty aid fifty years, 11 of the 40 eases were congenital in onset, 7 began in chilil- liood, arid iii 5 nodules had been observed more than ten years previously. L’rcsumably all eitses are congenital in origin. Multiple nodules (0.5 b’l0. 22. I~IGlI-POl~Elt ~’~IO‘l’OAlI(’R0GKAPII OF AX EDEMATOUS hfYXOID ~EUKINOMA Thc cells aic arranged in parallel ~0~8.Path. No. 47077. 395 396 OHAELES F. GESCHICKTER to 1 em. in diameter), freely movable and tender to pressure, situated on the trunk and extremities and accompanied by pigmentation were the outstanding features in most cases (Figs. 23 and 24). Involvement of the head and face was promiiient in 6 cases, and in an equal number nodules were found on the feet and hands. The tumors follow the distribution of the peripheral nerves and are often pedunculated. In one or more locatioris larger nodules, from 3 to 5 em. in diameter, may be palpated. The tumors along deeper nerves may give rise to rheu- matic pains for many years before becoming palpable. Thirty of the 40 patients in the present series had demonstrable involvement of the deep nerves or central tumors within the skull or along the spinal cord. Subcutaneous angiomatous lesions were present in 4 cases, spina bifids in 2 instances, curvature of both wrists in one, congenital club foot in FIG.23. PATIENT WITH VON RE('ICLINGIiAlJ8EN '8 DISEASE. PATII. NO. 4607 another, and hypertrophy of an extremity with plexiform neuromas three times. Nine of the 40 patielits with von Recklirighitusen's disease in the present series had sarcoma of a deep nerve trunk, proving fatal in each case. In 6 other patients tumors of the acoustic nerve, of the meninges, of the spinal roots within the vertebral caiial, or tumors within the mediastinum resulted in death. Ihtologically the superficial tumors are similar to the solitary subepidermal nodules of the nerre sheath (Figs. 2-27). The deeper tumors are myxoid neurinomas or sarcomas of the nerve sheath. Typi- cal palisaded neurinomas, however, were not observed in von Reck- linghausen's disease in this series except within the craiiiill cavity or along the spinal cord. Plelciforrn fieuiwtna or elephantiasis nervorum is coiisidered a form of congenital elephantiasis, since in the region affected the nerves, con- nective tissue, arid vessels may all show enlargement. In this type of FIG.24. PATIENTWITH VON RECRLINQHAUSEN 's DISEASE. PATH.No. 37818 From LLcwis and Hart: Ann. Surg. 92: 969, 1930. FIG. 25. PHOTOMICROGRAPHS SHOWING MELANOTIC(LEFT) AND NEURINOMATOUS (RIGHT) PORTIONSOF A SUBEPIDERMAL NODULE IN VON RECKLINGHAUSEN'S DISEASE. PATH.No. 20339 397 398 CHARLES F. GESCHICKTER nerve involvement, usually seen in von Recklinghausen’s disease, a limited part of the nerve is thickened and elongated as the result of an overgrowth of the sheath and connective tissue along the tortuous and FIG.26. PHOTOMICROGRAPH OF EORMAL FIBERSENTERINQ TIIE BEADEDAND THICKENED PO&- TION OF THE NERVE IN A CASE OF VON ~ECKLINQlIAUSEN’SDISEASE. PATH. NO. 30078 FIG.27. PHOTOMICROGRAPHOF A SARCOMA DEVELOPING BELOW POUPART’SLIGAMENT IN THE ANTERIORPORTION OF THE THIGH IN TIIE CASE SHOWN IN FIG.26 ‘ beaded course of the fibers. Lewis has reviewed the literature and discussed in detail this phase of the disease under the heading “ Ele- phantiasis Nervorum.” Bruns was the first to analyze a series of these cases, collecting 42 from the literature and adding 8 of his own. Lewis described 5 cases and stressed the enlargement of the part (Fig. TTJMORS OF THE PERIPHERAL NERVES 399 28) and the association of vascular and connective-tissue disturbances and a tendency for malignant tumors to develop on the involved nerve. These plexiform neuromas are essentially a forme fruste of von Reck- FIG.28. PATIENTAND GROSSSPECINENS FROM A CASE OF ELEPHANTIASISNERVORUM The left loner extremity is enlarged and the iiiultiple iiodules along the iierve which arc shown in the excised specimens were definitely palpable. From Lewis and Hart: Ann. Surg. 92: 976, 1930. linghausen's disease, since similar enlargements of the spinal nerves at their roots are often an outstanding feature in the more generalized form. The following ease is characteristic : A colored male, aged seventeen, was admitted to the hospital in August 1933, having noticed multiple nodules beneath the skin over the surface of the body for a little more than one year. IIe complained of pain in the left chest accompanied by increasing shortness of breath. A decided right scoliosis was present, with drooping of the left shoulder. The skin nodules, the largest of which were about 4 em. in diameter, followed the distribution of thc superficial nrrves about the body and down the extremities. The face, palms of the hands, and soles of the feet' were the only portions of the body free from these nodules. All of them were tender to pressure. The main physical findings pertained to consolidation in the left chest. X-ray revealed a large tumor in the medi- astinuni comprcssing the left lung. The neurological examination was essentially nega- tive. In January 1934 death occurred from respiratory embarrassment. Autopsy revealed in addition to the superficial nodules a lobulated tumor mass 18 X 12 X 12 cm. in the left chest. Numerous tumor nodules 1 em. in diameter followrd the distribution of the nerves along the trachea and esophagus. The sympathetic nerve chains anterior to the abdominal spine were thickened and beaded by tumor formation. Both the brachial plexus and the sciatic nerves were markedly thickened and beaded by numerous tumors. The roots of the thoracic and lumbar nerves showed bilateral tumor nodules. Nearly every spinal nerve at the intervertebral angle contained a tumor nodule slightly in excess of five mm. in diameter. Microscopic examination showed the nerve fibers of the'various spinal nerves separated by loose myxomatous tissue. The axis cylin- ders and myclin sheaths were visible in specially stained preparations in scattered fibers only. The mediastinal mass showed two types of tumor, one of these was typical nerve sheath sarcoma composed of interlacing strands of spindle cells, the other portion was epithelial in appearance and resembled a paraganglioma of the adrenal or, in places, para- thyroid tissue (Fig. 29). 400 CHARLES F. GESCHICKTER Sarcoma of the Nerve Sheath Sarcoma of the nerve sheath arises most commonly along the deep nerve trunks of the upper and lower extremities. The sites of occur- rence correspond very closely to the distribution of the benign deep myxoid neurinomas previously described. The lower extremity is more often affected than the upper, and the region of the popliteal space and the anterior arid posterior portion of the thigh are the most common FIG.29. PHOTOMICLtOGRAPH OF ~PI'PHEXJAI.-LII sites (Fig. 30). The iiicidencc of these tumors reaches its peak in the decade between thirty and forty ';years with approximately 10 per cent of the patients under twenty years (Fig. 4). The average duration of symptoms was slightly under one year in 75 per cent of the cases ; the remainder of the patients had known of a swelling or pain from five to fifteen years. The results of both the clinical and pathological study of the cases in the present series iiidicate that it large percentage of these sarcomas represent malignant change in pre-existing benign myx- oitl neurinomas. Histologically there is a remarkable degree of uniformity in the majority of these tumors. They are composed of tightly interlacing strands of plump spindle cells which may occasionally be elongated with wavy fibrils and at other times show enlarged nuclei with mitotic figures arid tumor giant cell formation. From this typical picture, which can be eoiieitlered Grade 11 or I11 sarcoma (Figs. 32 and 33), the tumors vary 011 the one hand toward the benign myxoid neurinomas, merging imperceptibly with the histological forms of this benign group TUMORS OF THE PERIPHERAL NERVES 40 1 (Fig. :Xi), which may be termed the Grade I sarcomas, and on the other hand a group showing ~iume~~oustumor giant cells and epithelioid forms, i*cpi*esc~iitiiigCriwlc) IV iii mdigiiniicy (Fig. 34). In 9 of the cases of this series, the malig~iaiic~ycomplicated von Becklinghausen’s disease. hi iiii cqual iinmlwr of wsw the nialigii~iitcliaiige occnrred in palisatled neiiriiioqas (Fig. 35). ‘I’hescl tumors recur after excision aid esteiid along the perineum1 lymphatic spaccs. Traiisplanitatioii by this route, rather than thc fo1.- FIG.30. TIIE (’OAIMON SITESOF NEKVESHEATH SAXCOMA matioii of iicw t iimory, seems Ihc most likely cxplaiiation of recurrciice. 13ccuusc of the local invasiveiiess aiitl the deep-seated location of thesc growths, bone iiivolveniciit (so-callccl parostcal sarcoma) is not an ii~i(~ornrnoiifiiicliiig ((+cscliicktci~). 1)ist;uit metastasis to lung or scalp or lm~inrather than to the regional lymph notlcs is o1)served in the fatal crises, Thi*cc ontstaiitling observatioiis as to trcatmciit are worth noting. First, the cured cwmiit this series either mi*etreated ly ampiitstion or were snpci-ficial tumors formc~rlyclassed as sar(*oma of the skin. b’W. 32. PHOTOMICROGRAPH OF (;KADE 11 SAK(‘ONA OF THE hTERVE SFIEATII. PATH. NO. 31775 402 b’IG. 33. PIIOTOBIICROGIRAPH OF GRADE111 SARCOMA OF TEE NERVESHEATH. PATH. NO. 39696 FIG.34. PHOTOYICROGRAPEOF GRADE 1V SAIWOAIAOF TIIE NERVESHEATH. PATH. No. 13152 403 404 ClIAltLES F. OESCHICKTER Second, irradiation did iiot produce a permanent cure when uscd alone, but in tlic recurrent tumors apparently delayed mettistasis or the spread of tlic disease in a small percentage of cases. Third, where the tumoi*s had invaded bone, or deeper structures such as the pelvis, no curw were effected. The prognosis of this form of sarcoma of the soft parts, arising from the nerve sheath, is far worse than that of fibrospindlc-wll siircorna of fascia1 origin, with which it is easily confiixecl histologicdy. Hist opicsis An interpretation of the histogenesis of these ncoplusms of tlic pei~ipliel*ulmi-ves s;houlcl account for the histologic diffeiwices hetween tlie palisticled iieui-iiiomas tuid the myxoicl form. It should also accon1it for the pcriplieral and central distribution of the tumors showing p.ali- suding, for their differentiation and fibrosis, for their encapsulatio~i, t heir occurrciicc in adults, and their benign clinical course. It should likewise explain the distribution of the myxoid neurinomas su1)epi- tlermally and on the deep nerve trunks, their lion-ciicapsulation, t2iei 1’ teridency to be multiple and congenital in von Rcckliiighauscii’s disww, their recurrence af - excision, and frequent malignant change. These fundamental differences iii behavior in the two groups 01’ tumors of the nerve sheath arc apparently relatcd to the presence or abseiice of a myclin sheath on the nerve fibers affected. 14ccor(ling to Nageotte, the myeliii exerts a. physiological cwiitrol over the cliartict(1r of the sheath of Sch\vaiiii. In the presence of mycliii individual tubular sheaths arc forrricel about each iie~*vefilm-, and small binidles of fihers ai*e surromided by pcrilieurium. 111 lion-myclinatcrl nei*vesin the syrn- Imthetic system, in the skin, and iii the coriiea, the sheath of Schwanri is multitubular, enclosiiig ;I. community of fibers in ii syricytial network. This is well il1ustr;itctl in the iierves of the corneal 1)lexus. I11 the chick ernbryo the nerves iiivide the cornea ill the form of a syricytial ar1)ol.i- zation. The network lying outside of the corzicti at the time of myclini- zation becomes mctlullated and is provided with iridiviclual sheaths. On tlie other hand, the neiiritcs of tlic cornea, iii older to maiiitairi tEic traiisparcncy of that organ, (lo not hecome metlnllatccl, aiitl n syncytial network or collective sheath iwriiiilis iil)oiit the c~)i*iicalplexus of fi1)ci.s. This intimate relationship which exists bctwcwi tlic myellin aiid tlicl slicath of Sc~liwaiiiialso exists l~e~tweeiitlic mycliii aiid lhe pcrincurium. Not only is the re-ari-augcmciit of the sheath of Scliwaiiii concu~-~+c~it wit21 the appearance of mycliri, hiit the periiicui*inm also forms at the time that myelin tipi)cvii*s. 111 the s1)seiice of myelinixiitioii a. commuiiity of riel-vc film-s within a syiicytium of Sch\vanii cells persists without a tlefiiiitc~priiicwrwl cii\do1)c, tlic c~oiinective-tissueslic~utli of tliesc? fibers remaining incomplete. rilhe pnlisiitletl iieiii*iiiomas il~)l)~1*(~litlyarise in connection with rnedullatcd nerves, tho slieatli of S(chwaiiii foi*miiig definite coluniris within the tumor at its inceptioii aiid bciiig eiicasccl by perineuriurn. The fibrous reaction of tlie peririenrinm accounts for the eiictipsulatioii TUMORS OF THE PERIPHERAL NERVES 405 and relatively bcriigri c~hai~acterof these growths. The coiitact of the tumor ;it its periphery with mycliiiatetl nerve fibers accounts for the 1)alisatlctl cficct. 11s tlic tumor grows, iieitlicr axoiis nor myelin par- ticipate ; liciice, tlic iiivtiriabl~~~i~~s~~iicc of syiicytial or reticulated areas $'IG. 35. ~IiOl'OhlI('ltOGILAPI1 OF SARCOMA DEVELOPINGIN A PALISADED NEIJRINOMA The tumor occurred in the popliteal spare and thc Icg was amputated. Previously pub- lished by Gcachic~kter. Path. No. 35248. within the center of the tumor. This relationship of the palisaded neurinomas to myelinatccl nerves accounts for their distribution in the subcutaneous pei*iphci*alnen-es and on the roots of the cranial and spiiial nerves. 406 CHAHLES E’. UESCIIICKTEH The myxoici neurinomas, on the other hand, tend to form in the subepidermal nerve fibers which are normally non-myelinated at their terminal ramifications. These tumors also occur on the non-medul- latetl visceral sympathctics, ant1 on the deep iierve trunks at the site of the larger iiww plexuses of the arm and leg. These plesuscs during cimbryonic life and early childhoot1 represent a syncytial network of sheath cells ~iidfibeias, where myelinizatiori is delayed. The origin of these tumoi-s in a syncytinm of Rchw;inn cells acconnts for their rcticn- ltitcd and iioii-r)alisatlctl iiixziigemeiit, for their failure to be erwiipsn- latcci by perinewiurn, anti for their tciitlciicy to irivaclc the more definite iubular strnctaiw in the nerve above a11d below tlie site of origin when they occur 0x1 the tlcbep nwves. In the snhcpidermaS tissue the conricc- tive tissue of the corinm i-eachto siirromicl the tumor, acting as a form of encapsulation. The assoc+iationof the mysoitl iieiiriiiomns with childhood is prob- ably related to dc1:iyc~tlmyclinization of the iierves. The occurrence of mu1tir)lc noclulcs of‘ this type iii the siq)erfic*ialand deep nerves in (~iswof voii 12cckli~igliaiiscn’stliscasc is liliewise prolmbly related to ii congenital c1isturl)aiicc in myclliiiizatioii at tlic sites of tumor formn- tion. That such ;tl)normalities iii mycliiiization occur in von Rec*kliiig- liaiiscii’s disease is tlcmoiist~~itctlhy the finding of mcclulluted nerve Gbcrs in tlic retina (Copeluxid, ct al). The interpretation just presented accepts the origiii of these tumors from the cells of the sheath of Scli\i~.aiin.Masson’s cytologicizl studies hive sliowi that the cdls in these tumors RI’C iclentical with the cells of the sheath of Schrvaiiii which piwlifcratc in the so-called cspei~irnenta1 scli~vaiinomits,first studied hy Nngeottc. If the sciatic nerve of it rabbit is cut thci*c is observcti 11~7 the foiirtli day clcgciicration of th~ distal films with mitotic proliferation of thc Scliwiiiii c~lls. If the proximal cnrS of the IICI*VC is removed, so ihat it c~iiiiiotiniicrvatc the distal segment aiiti it’ ;L scmntl cut is made in this c1ist:tl scgmciit, hypchi*- ti*opliy ant1 mitotic proliferation continue in the slicath of Schuwiiu. ‘l’hcsc ancnritic I)uiidlcs of i*egeiicratioii in the distal segmeiit aw iei*med c~xI)cr.irncxit:ils~hw~~i~iomas, and tlie indivithinl ccblls res;cmhl(i those seen iii the iiciiriiiomas of both the pidist-ltleti and noii-palisadevl varieties. Massori ldicivcls the collagen presciit to be a product of tlie Rchwaiin sllcatll rather thaii of fihroblilsts. Ilc llas suggested that palisading occiirs iii tlic tnmorx forming on seiisory iiervcs (simulatiiig \V;igiic~r-Mcissiicr tactile eoi+piiscles) and that rion-palisatlcti ncuri- tiomas occiir on motor iiei-vcs. In 1he Tissiie C’iilturc Laboratory of the Surgical Pathologicyd Lab oixtory Dr. G. 0. Gey has maintaiiicci for months cultuiw of malignimi nerve rslieatli tumors removed al operation. Tliesc cultures hehare cmtii-cly difTcreiitly and are histologically easily distinguished from cultures of IiorEiilI Iiuman fibroblasts (Figs, 3(j and 37). Besides tlic histological features of these tumors the1.c. are otllpr groiiiids for Idieving them of iicun*ogeiiic rather than of con~lcctive- tissue origin. The association of both lmiigii mid malig~ia~lttumors FIG.30. TISSUECIJLTURE FROM A SAIEO?,IAOF THE KERVESHEATH ’l’hr cells :in’ groniiig out iii a syiicytium. LTote the large vesicular nuclei. Compare mith E’igurc 37. Path. No. 45016. FIG.37. TISSIJECIJLTURE OF NORMALFIROBLASTS Notc tlir iiiterlacing network of cells and the dciise elongate nuclei. Goniparc with Fig we 36. Rlagiiific:ition same as in Fig. 36. 407 of this gi*oupwith melanoma, tlie fact that thy are associated anatom- ically with tlie iicrves illid tliat similar tumors do not occnr in the fascia1 striictiwes, aiid thcir maligiitint 1)chavior clinically, which ex- ccctls tlitit of fnscial tiimcws, :we in favor of a iicurogcnic origin. Fer- gi~son(cited by (hpclancl) has rcymrtccl the finding of intermediii in the hlootl of patients with rrinligiiaiit mclaiiomas, with von Reekling- liaiiscii’s disease, aiitl with nerve sheath sarcoma. The firiilirig of this mcliliiophorc-espaiidiiig Iiormonc of tlic pituitary in these patients is iii 1teey)ing with tlic nciurogeiiic origin of the tumors. In tlic pi’esc”nt scricis of cases 110 sharp dividing liiic csists bc4wccii tlich palisaclcd aiitl myxoid iieurinomas ant3 between the benign antl rnidipnit tumors, all of thcrri 1-epreseiiting various phases of iico- plastic growth in tlic slitvith of Sc1i~v:~nii.The contention of Pcrifieltl and others that tlic sul)cpidei.nial notlnlcs tire true ncurofibi*omas ant1 tliffcroiit in origin from tlie palisaded ticwriiiomas docs not seem jnstifia1)le. 111 s~vc~raliiistaiiccs iii this sei*ics a siiiglc noclnlch in tlic: su1)cpidcimal aiitl siilrciitaneoiis regioiis coritaiiictl lmth t ypcs of tissue. l*’iii~thermoi~,tho c~)iiceptionof ;L sepai*iitc group of tumors as tisollit1 ~ni(lfil)i*omatous in iiatiire (iwurofihroma) is contradicted hy tissue ciilture cxpci*imnits. 1t is ~vcllrccogiiixctl that ciiltares are easily mule of tlie wlls of tlic sheath of St’li\viiiiii, lint that without the PITS- ciic*c of sucli wlls tlic iieiii*iteswill not grow arid caiiriot he maiiitaiiietl iii c+iiltiit.c. ‘L’Ii(~ proliferation of siwh iwilrites, therefore, in the pres- cmcc of coiiiicctivc tissue oiily is liiglily hypothctical. It is doubtf ill wlicltlici- any iiciu*itcs iii the peripheral iiervoiis system exist without ;~iiaccompiiiigiiig sheath of Seliw\.;irin(Nageottc). ri1UMOHS IY~)~~il~~~~~(:NE~WEVIRERS : TRUE:NEUR~MAS Anap?ctcifiovi Arci~~~owns:Ti’ollo\ving the division of a main nerw by ;Irrlputiitioii or ii\tjiii*ya iieiiiwma forms on tlic proximal critl of tlic tlivitlctl iici’vc~. ‘l’liis m of i*cgeiiei~:ithgtissue (lifers from tumors of t lie iic~~veslicatli, coiit;iiiiiii(~*rcgciicixtiiig iiciirit cs as wcll as shcntli h of Schmmii cdls ;iii(i fihrous tissiic. ‘l’li~physiological details of ~ici*ve rcgeiieration leading to iicii iwma formation havc Iweri st utlicd in gi-cat dctail. ‘I‘hc followiiig tlesciiption is l~sctllaiyyly on the studies of Nagco t t c. Wli(’i1 R pei*iplicixl iicrv~t riiiik is scvci~ed,iicw cwllatcral sproiits 1)iwacetliiig fi.orn1 thci iicui+itcs (asoris) above tlic lesion appear R few lioiii*s aftcia thc i1i.jni.y. ‘l’hcy sooii form a plesus of non-mcdullatccl fihrs c~iicii~+lcd1)s’ ii syiicytiiim of piwlifcrating cells of the sheaths of Scliwiiiii oii tlic ~)i~)sininlsitlcl of thcl division. Newly formed co1111ec- tivcb tissnc. from t lic ciitloiiciii-iuni :uit’i pcririeiu*ium snpplies it stroma ;iiitl a fil)i~)usca;tl)snlcb c~iivc~lopsthe rcgcncratiiig mass, which is tcymecl a iit~iii~nria(li’ig. 1 ). l’hc growth of’ tlicl iichiiiwmtl is rapid ant1 tlis- oi.tl~i~1-yat fii-st hit giaatliially a i101~1~illoi*gnnizntion is rcsnmctl \trhcll thc tlonii-growiiig iicliiiitcs ciittLrt lie prolifcir:~tiiigsheaths of Schwann ~)i+oc*c~ctIirigfi.on1 tlic distal pi‘tioii of tlic sc\~crcdt ruiili. 1~lvclitually the ortlci*c~tliienritcs Iwomc mycliiiatcd. If, as in amputations, tile TUMORS OF THE PERJPHEHAL NERBES 409 ricuroma forming on the proximal stump fails to firid the channels of the sheath elements of the distal fragments and encounters instead resistant scar tissue, the proliferation of neurites, Schwain cells, antl coiiiiective tissue of the iieiiroma continue without myeliriization to form a typical painful ‘‘ amputation neuroma. ” Similar iieiiromas follow nerve injuries where scar tissue forms an impecliment to the regericrating fibers. The painful masses are treated by escision. In pcrfoi*ming amputation, injection of the iierre stump with alcohol prewnts the formation of these neuromas. hrewo-cpithelinl Tumors of the Peripheral Nerces: Tumors showiiig a primitive neuroblastic structure, while riot uncommoii in the neui*al structures of the sympathetic system, are cixtremely rare 011 the pe- ripheral spinal nerves. (kh1 1-cported a recnrreiit ncuro-epithelial tumor on the median nerve in a case of von Rccl\-lingli~nscii’sdisease in a man of thirty-five. Peiifield has illustrated a casc of Stout’s ill- volviiig the uliiar iicne antl showing definite rosette formation. These tnmors may represent undifferentiated forms of gaiiglioiicuroma, to which they are undoubtedly 1-elated. They do not \\rarrant a separate classification in view of the fact that the majority of all shcnth tnmors arisiiig from the Sclinmiii cells of the pcripheral UC~VCSai’c liltcwise iieuro-ectoclei.mN1in origin. Sarcomas of the nerve shcath, \vhich are liiglily maligiiaiit tiirnoi’s, are not iiifrccyueiitly see11 in which cells have ;LI~cipitliclit-il-like form or arrangemelit (Fig. 29). These cpi tliclioid l‘eaturcx of iieurogenic sarcoma wer*c noted in approsimat ely 10 per cent of thc cases of sarcoma in the present series. Stewart and Ckq~c- land fouiid similar microscopic variants in their cnses of sarcoma of the iier~esheath. Tlicsc epitlielioicl features in sarcoma of tlic nerve sheath tire additional cvidcncc in favor of tlic origin of these tumors from tlic sheath of Ck ( 11 Iwallll. Ga,/~~Zio~ieuro??7as:These are among the rarest tumors of the iiei*vous system. The majority of the 150 tumors recorded in the literntiire have oc~~iirrcdon the sympathetic nerves, most fiwluen tly in the regioii of the suprarenal glands. The 8 cases in the present sci-icls have been previously reported (1,ewis and Geschickter). They occnrml in the ~ousticnerve, mid-hrairi, cervieiil region (2), tl(lr~tli~1,thigh, aiitl finger. McFarlaiicl and Sappington have rcccrit 1- 1-cportetl a case and made a complete survey of the litcratixre. They were able to collect 143 C;LSCR,~ of wliich 41 n.cre r.citi.operitoiie;11or within the acli*enals, 18 were in the cei’vicvl, aiitl 10 iii the mcdittstiiial rcgioii. Fifteen cases were intracraiiial mtl 13 occurred on the craiiial nerves. Sis cases showed multiple snbcutaiicoiis tiini~rs,the maximum number of a single patient heing 160. One of the C;~SCS was associated with vori Rcckliiighausen’s disease. Many of tlw cases showed immature iienroblasts or iieuro- c’ytes, 10 of such cases being recoidetl as maligiiant. These tumors itre emhedded in a stroma of Sc~hwaiiiicells, and pali- sading may occasioiially be sec‘ii. Tlic giiiglioii cells vary from small to large mati1i.e forms aiitl occasioual ncnrites arc found. 3 These do not inc*luile the C:LSC~pre\,iouslg Icported by Lewis and Gcschicktcr. 410 CHAELES I?. GESCHlCKTER BIBLIOGRAPHY ANTONI,N. R. E. : Ueber Ruckciii~i;irl;sturnore~iuntl Neurofibrome, Miinchen and Wies- baden, 1920. BRUNS,P. : Ueber das Rankenneuroni, Beitr. z. klin. Chir. 8 : 1, 1891. COHEN,I. : Meningioma presenting trigeminal signs, Arch. Neurol. & Psychiat. 31 : 210, 1934. 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G. : Enibryonic transplantation and development of the nervous system, Anat. Rec. 2: 385-410, 1908. LEWIS, D., AND GERCHICKTER, C. F.: Tumors of the sympathetic nervous system, Arch. Surg. 28: 16, 1934. LEWIS, D., AND HART, L). : Tumors of the peripheral nerves, Ann. Surg. 92 : 961, 1930. MASSON,P. : Experimental and spontaneous schwaiinomas (peripheral gliomas) , Am. J. Path. 8: 367, 389, 1932. MUFARI~AND,J., AND SAPPINGTON,S. W.: A ganglioneuroma in the neck of a child, Am. J. Path. 11: 4‘29, 1935. NAGEOTTE,J. : Sheaths of the peripheral nerves, in Cytology and Cellular Pathology of the Nervous System, ed. by Penfield, New York, Paul B. Hoeber, Inc., 1932. Vol. I, p. 191. PEERS,J. H. : Primary intramedullary neurogenie sarcoma of the ulna, Am. J. Path. 10 : 811, 1934. PENFIELD,W.: Tumors of the sheaths of the nervous system, in Cytology and Cellular Pathology of the Nervous System, ed. by Penfield, New York, Paul B. Hoeber, Inc., 1932. Vol. 111, p. 955. RAYMOND,F., HUET,L., AND ALQUIER:Paralysie faciale phriphbriyuc due & un fibrosar- come englobant Ir nerf ti sortie bu bulbc, Arch. de neurol. 19 (ser. 3) : I, 1905. STALMANN,A. : Nerven- Haut- und Knochcnveriinderungen bei der Neurofibroma- tosis Recklinghuusen und ihre entstehungsgeschichtlichen Zusammenhiinge, Vir- chow’s Arch. f. path. Anat. 289: 96, 1933. STERNBERG,C. : Beitrag zur Kcrintnis der sogenunnten Geschwhlste des N. acusticus, Ztschr. f. Heilk. 21: 163-186, 1900. STEWART,F. W., AND COPELAND,M. Af. : Neurogenic sarcoma, Am. J. Cancer 16 : 1235, 1931. STOUT,A. P. : Peripheral manifestations of the specific nerve sheath tumor (neurilemoma), Am. J. Cancer 24: 751, 1935. VEROCAP, J. : Multiple Qcschwiilste als Systernerkrankung am mervosen Apparate, Fest- schrift f. Chiari, Vienna, 1908, p. 378. VIRCHOw, R. : Die Krankhnften Geschwnlstc~,Berlin, 1863. Vol. 111, p. 233.