A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center

ENIGN PNSTs include the schwannoma (also calledneurilemoma or neurinoma), the most common tu-mor arising from peripheral nerves, and the neuro-

fibroma.39 Malignant PNSTs (also known as neurogenicsarcomas) include malignant schwannomas and neurofibro-sarcomas, which are indistinguishable when viewed usinghistological techniques.

Peripheral neural sheath tumors are rare. Kransdorf32 re-ported 77 schwannomas of the wrist and hand, only 0.2% of39,179 soft-tissue tumors recorded by the US Armed ForcesInstitute.44 In several series, benign and malignant peripher-al nerve tumors of the arm and hand constituted only 1 to4.9% of all upper-extremity tumors.9,10,23,34,49,51 Stark, et al.,50

reported that malignant PNSTs account for 5 to 10% of soft-tissue sarcomas, which represent relatively few cases, and

malignant PNSTs have an incidence of 0.001% in the gen-eral population.6

Benign and malignant PNSTs occur sporadically as wellas in conjunction with NF1,22,42,46 an autosomal-dominantneurocutaneous disorder with an estimated incidence of onein 2500 births.17 Malignant PNSTs develop in 4 to 10% ofpatients with NF1.6,18

In the last 20 years surgically treated benign and malig-nant PNSTs have been described in case reports,1,21,24,25,33,47

small series,3,7,11,13,15,16,19,26,27,31,35,37–39,42–45,52 and large series.2,4,29,

40,48 To date the largest series have been composed of be-tween 79 and 119 patients. In the present paper, however,we review cases of 361 benign and 36 malignant tumors ofthe peripheral nerve and brachial and pelvic plexi, whichwere surgically treated over a 30-year period at LSUHSC.It is the largest series of neural sheath tumors of the periph-eral nerves and plexi in the literature and combines andupdates the earlier LSUHSC series.14,20,36 Tumors are cate-gorized according to neuroanatomical location and theirprevalence at each location is assessed. The number of spo-

J Neurosurg 102:246–255, 2005

246

A series of 397 peripheral neural sheath tumors:30-year experience at Louisiana State UniversityHealth Sciences Center

DANIEL H. KIM, M.D., JUDITH A. MUROVIC, M.D., ROBERT L. TIEL, M.D.,GREGORY MOES, M.D., AND DAVID G. KLINE, M.D.

Departments of Neurosurgery and Neuropathology, Stanford University Medical Center, Stanford,California; Department of Neurosurgery, Louisiana State University Health Sciences Center,New Orleans, Louisiana

Object. This is a retrospective review of 397 benign and malignant peripheral neural sheath tumors (PNSTs) that weresurgically treated between 1969 and 1999 at the Louisiana State University Health Sciences Center (LSUHSC). The sur-gical techniques and adjunctive treatments are presented, the tumors are classified with respect to type and prevalence ateach neuroanatomical location, and the management of malignant PNSTs is reviewed.

Methods. There were 361 benign PNSTs (91%). One hundred forty-one benign lesions were brachial plexus tumors: 54schwannomas (38%) and 87 neurofibromas (62%), of which 55 (63%) were solitary neurofibromas and 32 (37%) wereneurofibromatosis Type 1 (NF1)–associated neurofibromas. Among the brachial plexus lesions supraclavicular tumors pre-dominated with 37 (69%) of 54 schwannomas; 34 (62%) of 55 solitary neurofibromas; and 19 (59%) of 32 NF1-associat-ed neurofibromas. One hundred ten upper-extremity benign PNSTs consisted of 32 schwannomas (29%) and 78 neuro-fibromas (71%), of which 45 (58%) were sporadic neurofibromas and 33 (42%) were NF1-associated neurofibromas.Twenty-five benign PNSTs were removed from the pelvic plexus. Lower-extremity PNSTs included 32 schwannomas(38%) and 53 neurofibromas (62%), of which 31 were solitary neurofibromas and 22 were NF1-associated neurofibromas.

There were 36 malignant PNSTs: 28 neurogenic sarcomas and eight other sarcomas (fibro-, spindle cell, synovial, andperineurial sarcomas).

Conclusions. The majority of tumors were benign PNSTs from the brachial plexus region. Most of the benign PNSTsin all locations were neurofibromas, with sporadic neurofibromas predominating. Similar numbers of schwannomas werefound in the upper and lower extremities, whereas neurofibromas were more prevalent in the upper extremities. Despiteaggressive limb-ablation or limb-sparing surgery plus adjunctive therapy, malignant PNSTs continue to be associated withhigh morbidity and mortality rates.

KEY WORDS • neural sheath tumor • peripheral nerve tumor • schwannoma •neurofibroma

B

J. Neurosurg. / Volume 102 / February, 2005

Abbreviations used in this paper: CT = computerized tomogra-phy; LSUHSC = Louisiana State University Health Sciences Center;MR = magnetic resonance; NAP = nerve action potential; NF1 =neurofibromatosis Type 1; PNST = peripheral neural sheath tumor.

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radic tumors and tumors associated with NF1 for each tu-mor type is analyzed to determine whether there is a corre-lation among tumor frequency, type, and underlying genet-ic defect. Surgical techniques used for each type of benignPNST are brought together in one publication. The man-agement of malignant PNSTs is reviewed to complete theoverview.

Clinical Material and Methods

The charts of LSUHSC patients with 397 surgically treat-ed benign and malignant neural sheath tumors of thebrachial and pelvic plexi and the major peripheral nervesmanaged between 1969 and 1999 were evaluated, retro-spectively. The family history and physical and neurologi-cal examination findings of NF1 were documented. Tumorsize, location, mobility and localized tenderness on pal-pation, and the presence or absence of a Tinel sign wereassessed, and neurological deficits were determined by ap-plying the muscle strength and sensory grading systemsused at LSUHSC.14 Chest x-ray films were evaluated fortheir depiction of lower plexal tumors and plain x-ray filmsof the cervical spine were reviewed to find evidence ofintervertebral foraminal enlargement or vertebral erosion.Computerized tomography and/or MR imaging were per-formed to document tumor location, margins, and relation-ship to adjacent structures. For malignant PNSTs, the me-tastasis evaluation included lung and abdominal CT scansand technetium liver, spleen, and bone scans. Angiographicfindings of vascular tumors were noted to determine the de-gree of vascularity and to delineate the feeding vessels sur-rounding the tumor. Myelography results were includedwhen obtained to evaluate tumors involving the spinal ca-nal. Electromyography was performed in each patient inthis series. Histological diagnoses based on light micros-copy studies and at times electron microscopy studies fordifficult-to-diagnose cases were reviewed. The types of sur-gical and adjunctive treatments for benign and malignantPNSTs and the status of the surgical margins of malignantPNSTs were also assessed.

Immunohistological Methods

Immunohistological methods used in this series to dif-ferentiate Schwann and perineurial cells and endoneurialfibroblasts included S100 protein, which appears to be lessintense and less uniform in neurofibromas than in schwan-nomas,44 Leu-7, epithelial membrane antigen, vimentin, col-lagen, and neurofilament protein. Glial fibrillary acidic pro-tein was useful in approximately one third of the cases.34

These tests were used to decide whether a tumor had its ori-gin in the neural sheath.58

Surgery for Benign PNSTs of the Extremities

Despite differing degrees of fascicular involvement, sim-ilar surgical approaches were used for schwannomas, whichgrow extrinsic to their parent fascicles, and neurofibromas,which are intertwined with several fascicles of origin. Forboth types of tumor, the patient was positioned so that theinvolved limb’s response to electrophysiological stimula-tion could be observed.

Schwannomas. A lengthy longitudinal incision was madeover the tumor and the nerve or plexal element was exposed

at its entry and exit points in the tumor (Fig. 1A–C). The in-cision was extended down to the tumor capsule, and anoth-er longitudinal incision was then made between the fas-cicles, which were displaced and thinned out around thetumor. The fascicles were bluntly dissected off the tumorcapsule by using a fine-tipped double-ended or Rhoton dis-sector, a gauze-tipped hemostat (“peanut”), or the end of apair of Metzenbaum scissors. An interfascicular dissectionwas performed at the proximal and distal poles of the tu-mor, where usually one but sometimes two relatively smallfascicles were seen entering and leaving the tumor. Thesefascicles were isolated by using Vasoloops (Fig. 1D) andtested by stimulation and recording across the fascicle(s)entering and the fascicle(s) leaving each pole of the tumor.These NAP tracings were usually flat. The nonfunctionalproximal or distal fascicles were then sectioned and the tu-mor was usually removed as a single mass.

An alternative approach sometimes used in treating largetumors was to open the capsule longitudinally, enucleate theusually homogeneous and sometimes cystic tumor contentsby use of suction, forceps and scissors, or a Cavitron ul-trasonic surgical aspirator, and then dissect away and resectthe capsule away from the spared fascicles.

Neurofibromas. Neurofibromas had two or more enteringand exiting fascicles. These fascicles were usually largerthan those seen in schwannomas; however, tumor removalproceeded in the same manner as that used for schwan-nomas.

Neurofibromas usually had a capsule that was more ad-herent to the central mass of the tumor than was the casewith schwannomas. Larger tumors could be approached attheir proximal or distal ends, from underneath the lesionand above the inferior fascicles. The entering or exiting fas-cicles were then dissected free, sectioned, and used to ele-vate the tumor, allowing dissection of fascicular structuresaway from it until the opposite pole was reached.

As with schwannomas, an alternative approach was open-


Peripheral neural sheath tumors at LSUHSC

247

FIG. 1. A and B: Preoperative MR images demonstrating a radi-al nerve schwannoma in the left arm. C: Photograph showing theincision to be used for a posterolateral approach. D: Intraoperativephotograph showing the tumor prior to gross-total resection.

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ing and evacuating the tumor contents followed by dissec-tion of the capsule away from the fascicles.

Surgery for Benign Neural Sheath Tumors of theBrachial Plexus

An anterior supraclavicular approach was used to treat tu-mors involving roots and trunks. The infraclavicular ap-proach was used for lesions involving the cord and thoseextending from the cords to the nerves. Although the ante-rior supra- and/or infraclavicular approaches to the brachi-al plexus were used for most benign PNSTs of the brachialplexus, the posterior approach was used for tumor involve-ment at the following sites: 1) spinal nerves at an intrafora-minal level; 2) the C8–T1 roots; and 3) the lower trunk. Theposterior approach was also used in cases in which the pa-tient had undergone tumor resection and/or radiation thera-py with consequent severe scarring anterior to the plexus.

The plexal elements involved by tumor were identifiedand mobilized, and those uninvolved by tumor were isolat-ed and displaced. The involved and uninvolved fascicles atboth the proximal and distal poles of the tumor were alsoidentified by performing interfascicular dissection. Intraop-erative stimulation and recording of NAPs from involvedand uninvolved fascicles were performed and nonfunction-al fascicles were sacrificed. The remaining techniques werethe same as those described for schwannomas.

Surgery for Malignant PNSTs

Malignant PNSTs are rapidly growing, firm, and fixed le-sions presenting with either a progressive loss of function orsevere pain. An open biopsy was performed for lesions pre-senting in this fashion; if a malignant PNST was confirmed(Fig. 2), an evaluation for metastasis was carried out. Resec-tion was then performed in the following manner.

Brachial Plexus Malignant PNSTs. Resection of a malig-nant brachial plexus tumor varied depending on its originand location. Although total resection was the goal, this wasoften impossible without producing a severe vascular andfunctional loss; some loss also occurred by sacrifice of theelement of origin. Nevertheless, simple biopsy sampling ofsuch a lesion alone, without removal or substantial decom-pression, was not indicated. Amputation was seldom indi-cated at the time of the initial operation, because it was nec-essary to obtain permanent specimen sections from multiplesites to confirm the diagnosis of malignancy and to assessits invasion of adjacent structures.

Proximal Limb Malignant PNSTs. For malignant PNSTsinvolving a proximal limb, a wide resection would removevessels necessary for the preservation of the limb or adja-cent nerves. Amputation of the limb proximal to the lesionwas thus performed, but only after a frozen-section analysishad verified that the lesion was malignant and the metasta-sis workup had shown no evidence of distant spread of thedisease. When the diagnosis of malignancy was less certainbecause of less definitive pre- and intraoperative findingsand frozen-section results, only total removal of the tumorwas performed. Additional surgery was then dependent onthe histological findings of permanent sections and on pa-tient and family wishes.

Distal Limb Malignant PNSTs. For malignant PNSTs ofthe distal limb, depending on the extent of metastatic dis-ease, a wide local resection was performed. This includedremoval of the nerve, adjacent adherent soft tissues, and aseveral-centimeter margin of the entering and exiting nerve,all proving to be free of tumor on frozen and permanent tis-sue sections. This procedure usually led to a neural deficit.Depending on the morphological characteristics of the tu-mor, further options included intraoperative placement ofradioactive seeds in rods and postoperative external radio-therapy or chemotherapy alone or in combination.

In patients who refused surgery that went beyond an at-tempt to remove the lesion or in patients with metastatic dis-ease, irradiation of the limb with or without adjuvant che-motherapy was undertaken. In recent years, an attempt atlimb-sparing surgery has been favored whenever possiblefor sarcomas involving the extremities, but sometimes am-

D. H. Kim, et al.

248 J. Neurosurg. / Volume 102 / February, 2005

FIG. 3. Pie chart with a stacked bar graph showing the percent-ages of benign and malignant PNSTs and the distribution and re-spective percentages of the benign PNSTs. MPNSTS = malignantPNSTs.FIG. 2. Photomicrograph showing a malignant PNST. Most ma-

lignant schwannomas arise de novo and most malignant tumors arisefrom plexiform neurofibromas, the latter occurring in associationwith NF1. Mucopolysaccharide staining favors a malignant neurofi-broma over a schwannoma. Note the fibrosarcoma-like growth pat-tern demonstrated as intertwined fascicles of tightly packed hyper-chromatic spindle cells with tapered nuclei and faintly eosinophiliccytoplasm. Moderate to marked cytological pleomorphism, atypicalmitoses, and necrosis are usually identified. H & E, original magni-fication 3 200.

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putation or forequarter amputation is still performed (seeResults).

Results

Most of the 397 PNSTs that were surgically treated be-tween 1969 and 1999 were benign: 361 tumors (91%). Theremaining 36 tumors (9%) were malignant PNSTs (Fig. 3).

Incidence of Benign PNSTs

The most common benign PNST treated in this serieswas the neurofibroma: 237 (66%) of 361 tumors. Neurofi-bromas were more often solitary lesions and not associatedwith NF1 (141 tumors [59%]); however, the second mostcommon benign PNST was the neurofibroma associatedwith NF1 (96 tumors [41%]). Schwannomas accounted forthe remaining 124 benign PNSTs (34%).

Locations of Benign PNSTs

Benign PNSTs were most often located in the brachialplexus (141 tumors [39%]). The upper and lower extremi-ties were the locations of 110 (30%) and 85 (24%) tumors,respectively (Fig. 3 and Table 1).

Brachial Plexus Schwannomas and Neurofibromas. Most

of the 141 benign tumors of the brachial plexus were neu-rofibromas (87 tumors [62%]); these included 55 sporadicsolitary neurofibromas (63%) and 32 neurofibromas re-moved from patients with NF1 (37%) (Table 1). The tumorsassociated with NF1 were completely removed in 18 cases(56%) and partially resected in 14 cases (44%). Sixty-twopercent of the solitary neurofibromas and 59% of the NF1-associated neurofibromas were located in the supraclavic-ular region; 25% of the solitary neurofibromas and 25% ofthe NF1-associated neurofibromas were located infraclavic-ularly. Schwannomas were less common than neurofibro-mas in this region: 54 schwannomas (38%) compared with87 neurofibromas (62%). Most schwannomas of the bra-chial plexus region (37 [69%] of 54 tumors) were locatedsupraclavicularly and only nine (17%) were located infra-clavicularly.

Schwannomas and Neurofibromas of the Upper Extremities.Most tumors of the upper extremities (78 [71%] of 110)were neurofibromas. These included 45 sporadic solitaryneurofibromas (58%) and 33 NF1-associated neurofibro-mas (42%). Twenty-one sporadic solitary neurofibromas(47%) involved the ulnar nerve; 19 (42%), the mediannerve; and five (11%), the radial nerve. Of the NF1-associ-ated neurofibromas, 15 (45%) were removed from the ulnarnerve, 11 (33%) from the median nerve, and seven (21%)from the radial nerve (Fig. 4 and Table 1).53

Thirty-two (29%) of 110 benign PNSTs in the upper ex-tremities were schwannomas (Table 1). Of these, 17 (53%),were removed from the median nerve, eight (25%) from theulnar nerve, and seven (22%) from the radial nerve.

Schwannomas and Neurofibromas of the Pelvic Plexus. Ofthe 25 benign PNSTs of the pelvic plexus, 19 (76%) wereneurofibromas, including 10 sporadic solitary lesions andnine tumors associated with NF1; six tumors (24%) wereschwannomas (Table 1).

Schwannomas and Neurofibromas of the Lower Extremi-ties. There were 85 PNSTs (Fig. 5) in the lower extremities(Table 1). Neurofibromas were found in the lower extrem-



249

TABLE 1Locations of 361 benign neural sheath

tumors in the LSUHSC series*

Sporadic NF1-Solitary Associated

Location Schwannoma Neurofibroma Neurofibroma Total

brachial plexus region 54 55 32 141supraclavicular 37 34 19 90infraclavicular 9 14 8 31axillary nerve 3 4 4 11musculocutaneous 3 2 1 6

nerveother 2 1 0 3

upper extremity 32 45 33 110ulnar nerve

arm 5 10 8 23elbow/forearm 2 8 3 13wrist/hand 1 3 4 8

median nervearm 7 10 5 22elbow/forearm 4 6 3 13wrist 6 3 3 12

radial nervearm 5 2 3 10elbow 1 2 2 5PIN/SSRN 1 1 2 4

pelvic plexus 6 10 9 25lower extremity 32 31 22 85

femoral nerve 5 7 2 14sciatic nerve

buttock 2 4 3 9thigh 8 9 6 23

tibial nerve 10 5 5 20peroneal nerve 4 4 3 11saphenous nerve 2 1 0 3sural nerve 1 0 2 3obturator nerve 0 1 1 2

* PIN = posterior interosseous nerve; SSRN = superficial sensory radialnerve.

FIG. 4. Photomicrograph showing a neurofibroma. There are thecharacteristic haphazardly arranged neoplastic Schwann cells, peri-neural-like cells, and fibroblasts present in a background of colla-gen fibers and mucosubstance. A “shredded carrots” appearance isnoted in tumors with prominent collagen formation. H & E, origi-nal magnification 3 100.

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ities in 53 patients (62%); 31 (58%) of these lesions weresporadic solitary neurofibromas and 22 (42%) were asso-ciated with NF1. Most sporadic solitary lesions (13 [42%])and most NF1-associated neurofibromas (nine [41%]) werelocated in the sciatic nerve. Of 13 sporadic solitary neurofi-bromas of the sciatic nerve, nine (69%) were found at thethigh level and four (31%) at the buttock level. More neu-rofibromas in patients with NF1 were located at the thighlevel (six lesions [67%]) than at the buttock level (threelesions [33%]).

Schwannomas were removed from 32 patients (38%).Ten (31%) of these lesions involved the sciatic nerve and 10(31%) involved the tibial nerve. Eight of the 10 sciatic nerveschwannomas were located at the thigh level and two werelocated at the buttock level.

Preoperative and Intraoperative Characteristicsand Outcomes

Benign PNSTs characteristically presented with pain,which occurred more frequently in patients with neurofibro-mas than in those with schwannomas.

Benign PNSTs usually included an eccentric oval massthat had been present for some time in a deep location in thecourse of a nerve or plexal element. On palpation, the mass-es could be moved laterally, but not longitudinally in the di-rection in which the tumor extended. Percussion over themass caused paresthesias in the distribution of the involvednerve in most patients with schwannomas and almost all pa-tients with neurofibromas.

Schwannoma. If the tumor caused pain or weakness, itwas removed (Fig. 5) to preclude neurological sequelaefrom tumor enlargement and, less frequently, to improvecosmesis. Careful resection of schwannomas usually re-solved the patient’s symptoms. Regardless of the nervefrom which a schwannoma arose, baseline function afterresection could be preserved the majority of the time. In

a representative sample of 76 patients with schwannomaswho were included in the present series, baseline functionwas preserved or improved 89% of the time.14

Sporadic Solitary Neurofibromas. Management of neurofi-bromas not associated with NF1 was based on the patient’ssymptoms. Asymptomatic neurofibromas were often man-aged with observation. Resection was indicated for tumorsthat caused pain or progressive neurological deficits, and forthose lesions with an uncertain diagnosis or for which ma-lignancy was suspected.

Solitary neurofibromas could also be excised withoutproducing a deficit if an interfascicular approach was usedsupplemented by NAP testing of the fascicular structure.Eighty-five percent of 99 solitary neurofibromas (whichwere part of the present series) were excised without anyloss of normal preoperative function or patients improved.14

Neurofibromas Associated With NF1. In patients with NF1there is a 15% risk of malignant degeneration and thus thesetumors should be removed when they become symptom-atic. The NF1-associated neurofibromas were excised inmost cases without producing a serious deficit even whenthey involved a major nerve.

Owing to the more difficult dissection of neurofibromasin patients with NF1, resolution of symptoms was often notas good as that in patients without NF1. Nonetheless, in 48patients with NF1 in whom neurofibromas were resected,83% had stable or improved motor function.14 Becauseneurofibromas in patients with NF1 are more likely to beplexiform, the incidence of total resection was 76%, ascompared with all tumors in patients harboring solitary neu-rofibromas.14

Plexiform Neurofibromas. Surgical treatment of plexiformneurofibromas (Fig. 6) was difficult, but it was possiblewhen there were good indications such as symptomatictumors involving sensory nerves or branches. Completeremoval generally was not possible without a loss of neu-

D. H. Kim, et al.


FIG. 5. Upper and Lower Left: Magnetic resonance images revealing a peroneal tumor, which on histological examina-tion was found to be a schwannoma. Right: Photomicrograph showing a section of the schwannoma with its spindle-shaped neoplastic Schwann cells. Shown is an Antoni A area characterized by alternating areas of compact, elongated cells.A Verocay body is seen centrally; its nuclear palisades are formed by roughly parallel arrays of tumor cell nuclei separat-ed by dense, closely aligned cell processes and basement membranes. H & E, original magnification 3 200.

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rological function and, in some cases, even subtotal remov-al of a plexiform tumor led to some loss of function. Nervesection proximal and distal to the lesion followed by repairof the often lengthy gap did not usually restore function. Forlarge tumors or in cases in which severe pain was a dom-inant symptom, decompression with removal of a portionof the tumor bulk provided benefit. In selected cases, itwas possible to reduce pain by decompressing the nerve in-volved by the tumor by neurolysis, especially if the nervewas in a usually closely confined area such as behind the el-bow or knee or in the carpal tunnel or the Guyon canal. Tu-mors involving less important sensory nerves or branches,such as the antebrachial cutaneous, superficial sensory ra-dial, sural, or saphenous nerves, could be totally removed,along with the nerve of origin.

Plexiform neurofibromas may be solitary non–NF1-asso-ciated lesions, but they are more likely to be associated withNF1. A solitary plexiform tumor may also be accompaniedby hundreds of smaller neurofibromas involving the nerveof origin of the large lesion. These associated tumors in-volve the nerve proximal and distal to the large lesion and,occasionally, other nerves in the same limb in a syndromeknown as “regionalized NF1.” Only a palliative surgicalprocedure can be performed in these situations.

If the plexiform tumor is large and firm, removal can beconsidered to ensure that malignant transformation is notpresent, a process that occurs in 5% of plexiform neurofi-bromas and is usually marked by significant pain and rapidgrowth. A second operation for neural sheath tumors, forwhich repair is necessary, requires a frozen-section biopsyof nerves or elements of origin to ensure that residual tumoris not incorporated in the repair.

Incidence of Malignant PNSTs

Of the 36 malignant PNSTs of the brachial and pelvicplexi and the major peripheral nerves, 28 (78%) were neu-rogenic sarcomas and eight (22%) were other sarcomas,such as fibrosarcoma and spindle cell, synovial, and peri-neurial sarcomas (Table 2). Of the 28 neurogenic sarcomas,16 (57%) were solitary tumors in patients without NF1 and12 (43%) were found in patients with NF1.

Locations of Malignant PNSTs

Brachial Plexus Malignant PNSTs. The brachial plexuswas the location in which the majority (21 [58%] of 36) ofsarcomas were found. Of 21 brachial plexus neurogenic andother sarcomas, 13 (62%) were not associated with NF1 andeight (38%) were associated with NF1.

Preoperative and Intraoperative Characteristicsand Outcomes

Pain with or without a progressive loss of function andparesthesias in the distribution of the involved nerve werethe most common presenting complaints in patients withmalignant PNSTs. Some patients noticed a lump that waspainful when it was palpated or bumped. In other cases,an initial mild loss of function rapidly became severe. Rare-ly, these patients presented initially with metastasis to lung,bone, liver, and/or spleen.

Despite some differentiating features on the physical ex-amination, the majority of malignant PNSTs were not sus-

pected of being malignant until biopsy or their attemptedremoval. Either procedure in relatively inexperienced handscan lead to a neural loss, just as occurs with more benignPNSTs. Neural loss is more likely with malignant tumorsthan with benign ones, not only because of their more in-trinsic nature in relation to the nerve or element of origin,but also because of their adherence to adjacent neural struc-tures and to other soft tissues such as vessels, muscle, andeven bone.

Twenty (56%) of 36 patients with neurogenic and othersarcomas underwent a local resection of the lesion. Sixteen(44%) of 36 underwent a local resection with margins. In 10patients (28%) forequarter amputations of the shoulder andarm or hip disarticulation were performed and in three pa-tients (8%) amputations of extremities were performed.

Adjunctive Treatment and Survival. Twenty (56%) of 36patients with malignant PNSTs received radiation therapyand in four patients (11%) radioactive seeds in rods wereplaced. Twenty-two (61%) of the 36 patients died; these pa-tients had survived an average of 25 months before suc-cumbing to their diseases.

Discussion

Location Preference and Causes of PNSTs

The causes of benign and malignant PNSTs remain un-known. Hereditary disorders such as NF1 predispose tobenign PNSTs and NF1 presages half of the cases of ma-lignant PNST. Neurofibromatosis Type 1 is caused by mu-tations in the NF1 gene on chromosome 17 and the gene’sprotein product, neurofibromin, functions as a tumor sup-pressor.17,54,55,59,60 The majority of the 361 benign PNSTs inthis series were neurofibromas (237 lesions). Of these 237neurofibromas 141 tumors (59%) were sporadic neurofibro-mas not associated with NF1 and 96 tumors (41%) wereassociated with NF1. Of the 28 neurogenic sarcomas, 57%were found in patients without NF1 and 43% in patientswith NF1. Although not a majority for either benign or ma-lignant tumors, the NF1-associated neurofibromas still rep-



251

FIG. 6. Intraoperative photograph showing a plexiform neuro-fibroma of the posterior interosseous nerve. This type of neurofi-broma is associated with NF1. Neurofibromas can also be solitary(sometimes called “fusiform” or “globular”), which are occasional-ly associated with NF1.

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resented a high percentage of the neurofibromas in thisseries.

There are sporadic reports of schwannomas associatedwith previous trauma,12,57 and trauma has been proposed totrigger the formation of a neurofibroma.5,28,41 Yla-Outinen,et al.,60 has demonstrated that NF1 gene expression is upreg-ulated during wound healing in humans who do not haveNF1. Thus, trauma may play an added role in addition togenetics in the formation of these tumors.

Kim, et al.,30 recently showed that among 509 stretch/contusion injuries of the brachial plexus due to motor vehi-cle accidents, 366 (72%) were in a supraclavicular locationand only 143 (28%) were in the infraclavicular region. Thesupraclavicular region is thus more susceptible to trauma. Itis interesting that in the present series 69% of schwannomasof the brachial plexus region were supraclavicular and on-ly 17% were infraclavicular. This was also true for bothsporadic and NF1-related neurofibromas, in which 62 and59%, respectively, were supraclavicular and 25% for bothtypes were infraclavicular in location. Also, the pelvic plex-us is located in a well-protected site, compared with thebrachial plexus, and harbored far fewer schwannomas (six[5%] of 124) and neurofibromas of both the sporadic (10[7%] of 141) and NF1-associated (nine [9%] of 96) types.Thus, in the brachial plexus schwannomas (54 [44%] of124) and neurofibromas of both the sporadic (55 [39%] of141) and NF1-associated (32 [33%] of 96) types were moreprevalent. This may represent another example of a traumacomponent involved in the generation of schwannomas andneurofibromas.

The current findings also indicate that these tumors haveother predilections for growth in certain anatomical loca-tions. Benign PNSTs were most often located in the brachialplexus (39%) followed by a slight preponderance in the up-per extremity (30%) compared with the lower extremity(24%). Most of the benign tumors of the brachial plexus re-gion and the upper and lower extremities were neurofi-bromas: 62, 71, and 62%, respectively. The brachial plexuswas the dominant site for metastases, with 88% of malig-nant PNSTs removed from this location. The significance ofthis is not known at this time.

Malignant PNSTs or Neurogenic Sarcomas

Several groups experienced with soft-tissue sarcomas ofvarious types involving the upper or lower extremity havedeveloped programs for limb salvage.8 This usually in-cludes a wide local resection of the tumor and adjacent tis-sues, leaving a several-centimeter margin of soft tissue andentering and exiting nerve free of tumor on frozen and per-manent tissue sections. This surgery is followed by localsoft-tissue irradiation, which can be accomplished using im-planted radioactive seeds, radiotherapy, and/or chemothera-py. Usually, the two major options are discussed with thepatient and family members, and a decision favoring oneapproach or the other is made. In the last decade, our expe-rience with the limb-sparing approach, which includes widelocal resection followed by seed irradiation, has been favor-able, but a larger series of cases with a follow-up review be-yond 5 years is needed.

At a plexal level, amputation is another option, and thishas given the longest survival for patients with NF1- andnon–NF1-associated distal plexus malignancies. Therewere only three amputations in the present LSUHSC se-ries—too few to draw meaningful conclusions. Those le-sions located more proximally and arising from the plexuswere treated with as thorough a resection as possible andnot with a wide local resection, because that would have re-sulted in a flail as well as devascularized arm. Such a resec-tion was followed by radiation treatment and also by che-motherapy in several cases. The management plan followedat LSUHSC agrees with those outlined in the literature.Casanova, et al.,11 presented a review of 24 pediatric pa-tients with malignant PNSTs treated during a 20-year peri-od. Primary radical surgery without adjuvant therapy wasperformed in 10 patients. Postoperative radiotherapy alonewas administered in 12 cases and postoperative adjuvantchemotherapy in 19. Eight patients were alive without evi-dence of disease; in six there was a first complete remissionand in two a new complete remission after a median follow-up period of 230 months. The 10-year event-free survivalrate was 29% and the overall survival rate was 41%. Surviv-al at 10 years was 80% for patients who underwent com-plete resection and 14% for others who underwent subto-

D. H. Kim, et al.


TABLE 2Treatment of 36 malignant PNSTs in the LSUHSC series*

Sporadic NF1-Type of Tumor Solitary Associated RT w/ No. of

& Location Neurofibroma Neurofibroma LR LRM RT Seeds in Rods Amp 4-Qtr Amp Mean FU Deaths (MPS)

neurogenic sarcomasbrachial plexus 10 7 11 6 8 0 1 6 52 14 (25)ulnar 2 0 0 2 1 1 0 0 52 1 (37)sciatic 2 2 2 2 1 1 0 3 32 2 (16)femoral 1 1 0 2 1 1 1 0 46 1 (16)peroneal 1 1 0 2 2 0 0 0 48 0 (NA)tibial 0 1 1 0 1 0 1 0 50 0 (NA)

other sarcomas†brachial plexus 3 1 4 0 4 0 0 0 47 2 (40)sciatic 2 0 2 0 1 0 0 0 27 1 (12)femoral 1 0 0 1 1 0 0 1 18 1 (18)peroneal 1 0 0 1 0 1 0 0 28 0 (NA)

totals 23 13 20 16 20 4 3 10 46 22 (25)

* Amp = amputation; LR = local resection; LRM = local resection with margin; MPS = mean postoperative survival in months; NA = not applicable; RT =radiation therapy; 4-Qtr = forequarter of the shoulder and arm or hip disarticulation.

† Includes fibrosarcomas and spindle cell, synovial, and perineurial sarcomas; excludes Ewing sarcoma.

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tal resection. With regard to tumor size, the 10-year surviv-al rate was 71% for patients with tumors smaller than 5cm and 29% for those with tumors 5 cm or larger. Completeexcision remained the most effective treatment for malig-nant PNSTs and was the main prognostic factor along withtumor size. Radiotherapy seemed to play a role in achievinglocal control, whereas the role of chemotherapy was uncer-tain.

A study by Wanebo, et al.,56 of 28 cases of malignantPNSTs found a median disease-free survival time of 11months and a median overall survival time of 44 months.The approach of these investigators was aggressive surgerywith wide surgical margins combined with adjuvant radia-tion therapy. Chemotherapy was thought to have a possiblerole for treatment failures.

Stark, et al.,50 reported eight cases of malignant PNSTs.All patients underwent surgery with the intent to cure thedisease, but total resection defined by negative surgicalmargins was achieved in only three cases. All patients ex-perienced a local recurrence of the disease with a meandisease-free survival time of 10.6 months. In five cases ad-juvant radiotherapy was given. In three patients distant me-tastases developed and five of eight patients died during thefollow-up period, with a mean survival time of 11.6 monthsafter diagnosis. The authors concluded that the prognosisremains dismal despite multimodal therapy including resec-tion and adjuvant radiotherapy including brachytherapy.

Conclusions

In this paper we have presented a large series of benign(91%) and malignant (9%) PNSTs. Neurofibromas can of-ten be removed using fascicular dissection at the poles ofthe tumor to spare all but the fascicle(s) entering and exitingthe tumor mass, as well as to spare the more peripherallydisplaced fascicles. Nerve action potentials are monitored toconfirm the usually nonfunctional nature of the entering andexiting fascicles. Thus, these fascicles can be resected, anda large lesion, even a neurofibroma, can be removed as asolitary mass in most instances.

Neurofibromas were the most common benign PNSTs(66%) and schwannomas comprised 34% of the benignPNSTs (Table 3). Most benign PNSTs were located in thebrachial plexus (39%), and 62% of tumors in this location

were neurofibromas of which 63% were sporadic and 37%were associated with NF1. Most solitary (62%) and mostNF1-associated (59%) neurofibromas were located in thesupraclavicular brachial plexus and the remainder were inan infraclavicular location. The upper and lower extremitiesharbored 30 and 24% of benign PNSTs, respectively: in theupper extremities 71% (58% sporadic and 42% NF1-asso-ciated) of tumors were neurofibromas and in the lower ex-tremities 62% (58% sporadic and 42% NF1-associated) oftumors were neurofibromas. Schwannomas comprised 29%of tumors in the upper extremities and 38% of tumors in thelower extremities. The pelvic plexus harbored 25 tumors:24% were schwannomas and 76% were neurofibromas (10sporadic and nine NF1-associated tumors).

Most sarcomas (21 [58%] of 36 lesions) were located inthe brachial plexus. Fifty-six percent of patients with ma-lignant PNSTs underwent radiation therapy and in 11% ra-dioactive seeds in rods were placed. Twenty-two (61%) of36 patients died; these patients survived an average of 25months before succumbing to their disease. The manage-ment of neurogenic sarcomas is thus less satisfactory. De-spite either aggressive limb-ablation or limb-sparing sur-gery with heavy adjunctive therapy, these tumors continueto be associated with high morbidity and mortality rates.Surgical approaches involving decompression as well as themost complete removal possible, however, remain the es-sential initial step for treatment of most malignancies of theperipheral nerves.

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TABLE 3Summary of benign and malignant PNSTs

Location

Tumor Type Total No. BP UE PP LE

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neurogenic & other sarcomas 13 8 0 0 5

* BP = brachial plexus; LE = lower extremity; PP = pelvic plexus; UE = upper extremity.

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Manuscript received January 8, 2004.Accepted in final form September 9, 2004.Address reprint requests to: Daniel H. Kim, M.D., Department of

Neurosurgery, Stanford University Medical Center, Room R-201,Edwards Building, 300 Pasteur Drive, Stanford, California 94305–5327. email: [email protected].



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A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center