Case Report

Schwannoma With Rhabdomyoblastic DifferentiationA Unique Variant of Malignant Triton Tumor

Ö Kurtkaya-Yapıcıer, B. W. Scheithauer, J. M. Woodruff, D. D. Wenger,A. M. Cooley, and D. Dominique

A 54-year-old woman presented with intractable perianal, bi-lateral buttock, and radiating thigh/calf pain. An MRI scanshowed an intradural, contrast-enhancing, ovoid mass in thecauda equina region at L1–L2. At laminectomy, the ovoid massarose from a nerve root and, intact, was gross totally resected.Histologically, the dominant pattern was that of schwannoma.One year thereafter, the symptoms recurred. An MRI scan dem-onstrated an irregular, heterogeneously enhancing tumor recur-rence. A repeat laminectomy disclosed a large fleshy tumorinvolving multiple nerve roots. The lesion was subtotally re-sected and showed pluridirectional differentiation toward em-bryonal rhabdomyosarcoma, primitive neuroectodermal tumor,and rare malignant epithelial cells. Review of the original tu-mor disclosed only foci of embryonal rhabdomyosarcoma andprimitive neuroectodermal tumor. Based upon available dataregarding divergent differentiation in peripheral nerve sheathtumors, this is a unique, previously undescribed tumor demon-strating rhabdomyosarcomatous, primitive neuroectodermal tu-mor and scant epithelial differentiation in a schwannoma. Inessence, it is a variant of malignant Triton tumor because of itsorigin in a tumor consisting of well-differentiated Schwanncells. It supports the contention that the Schwann cell is thesource of a variety of heterologous elements in nerve sheathtumors.Key Words: Malignant peripheral nerve sheath tumor—Primitive neuroectodermal tumor—Schwannoma.

Am J Surg Pathol 27(6): 848–853, 2003.

Divergent differentiation in nerve sheath tumors mostoften takes the form of rhabdomyosarcoma within thesubstance of a malignant peripheral nerve sheath tumor

(MPNST). Such lesions are termed malignant Triton tu-mors,25,27 referring to the studies of Masson who postu-lated that divergent myoid differentiation could occur inneoplastic neuroectodermal cells.15,16 In approximately15% of cases, osseous and/or cartilaginous elements oreven a variety of epithelia may be observed (pluridirec-tional differentiation).6 The process is not limited toMPNST. Histologically benign striated muscle differen-tiation has also been reported in a neurofibroma of thevagina.1 Herein, we report a unique example ofschwannoma undergoing transformation to embryonalrhabdomyosarcoma in addition to primitive neuroecto-dermal tumor (PNET) cells and cells with an epithelialimmunophenotype (pluridirectional differentiation). Thefinding underscores the differentiating potential of neo-plastic Schwann cells and indirectly confirms theschwannian origin of heterologous differentiation inMPNST and rarely neurofibroma.4,30

CASE REPORT

The patient, a 54-year-old white woman, presentedwith a 7-day history of intermittent perirectal and bilat-eral buttocks pain that was sharp in nature and exacer-bated with movement. On the day prior to emergencyadmission, the pain became intense and radiated downboth legs to the level of the ankle. The patient was am-bulatory at the time of admission. Despite a 10-mg in-jection of intramuscular morphine, no pain relief wasnoted. She remained supine and strictly avoided move-ment. A clinical history indicated she was married, themother of two children, and a nonsmoker. The familyhistory was noncontributory; her mother had died ofcancer secondarily involving bone and her father ofParkinson disease. A brother was alive and well. Therewas no family history of central nervous system neopla-sia or of neurofibromatosis types 1 or 2. A general, some-

From the Department of Laboratory Medicine and Pathology (O.K.-Y.,B.W.S.) and Diagnostic Radiology (D.D.W.), Mayo Clinic, Rochester,Minnesota; Marmara University School of Medicine (O.K.-Y.),Institute of Neurological Sciences, Istanbul, Turkey; Memorial SloanKettering Cancer Center (J.M.W.), New York City, New York; andthe Departments of Pathology (A.M.C.) and Surgery (D.D.), AltruHospital, Grand Forks, North Dakota, U.S.A.

Address correspondence and reprint requests to B. W. Scheithauer,Department of Laboratory Medicine and Pathology, Mayo Clinic, 2001st St. SW, Rochester, MN 55905, U.S.A.; e-mail:scheithauer.bernd@mayo.edu

The American Journal of Surgical Pathology 27(6): 848–853, 2003 © 2003 Lippincott Williams & Wilkins, Inc., Philadelphia

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what limited physical examination was unrevealing. Vi-tal signs were normal, and there were no cardiorespira-tory symptoms, organomegaly, adenopathy, or massesinvolving rectal/perirectal soft tissue. A neurologic ex-amination, again limited, revealed no abnormality. TheMRI examination demonstrated a large, intradural extra-medullary mass in the spinal canal in the region of thecauda equina just distal to the conus at L2–L3 (Fig. 1A).The mass had nonspecific signal characteristics with lowsignal intensity on T1, primarily high signal on T2, anddiffuse enhancement with gadolinium. There was acentral focus of low signal intensity on the T2 andgadolinium-enhanced images. The differential diagno-sis for a mass in this anatomic location with theseimaging features would include schwannoma, meningi-oma, ependymoma, and metastatic disease. The centralfocus of low signal intensity seen within this hyperin-tense lesion on the T2-weighted images has been de-scribed as a characteristic MRI feature of neurilemmomaor neurofibroma, indicating that this could represent aschwannoma.

At surgery, an L1–L2 laminectomy, no abnormalitiesof bone or the epidural space were noted. Upon opening

the dura, intradural adhesions were evident and requiredlysis. The tumor, an ovoid, smooth-surfaced mass, wasseen to arise from a nerve root, which was splayed overits surface. The involved nerve was divided proxi-mally and distally. The lesion was delivered intact. Four-teen months thereafter, the patient presented after a2-week history of severe, intractable, low back painworsened by movement. Increasing leg weakness wasevident, but no abnormalities of bowel or bladder func-tion were noted. The follow-up MRI demonstrated arecurrent ovoid mass in the operative bed of the previ-ously resected lesion (Fig. 1B). The mass had similarsignal characteristics with low signal intensity on T1 andhigh signal intensity on T2. However, the mass wasslightly larger in size than the previous mass and dem-onstrated an increase in lesion heterogeneity and marginirregularity on the T2-weighted and gadolinium-enhanced images, features suggestive of a malignant le-sion or malignant degeneration of a previously benigntumor. At surgery, again an L1–L2 laminectomy, a yel-low–gray tumor bulged from the dural incision. A grosstotal removal of tumor lying between levels L1 and 2was achieved.

FIG. 1. Sagittal T1-weighted images with fat saturation and gadolinium (A) demonstrate a large well-circumscribedintradural extramedullary mass in the spinal canal just distal to the conus in the region of the cauda equina at L2–L3. Thereis a small central focus of low signal intensity within the hyperintense lesion on the gadolinium-enhanced image. Therecurrence on sagittal T1-weighted images with fat saturation and gadolinium enhancement (B) obtained 14 monthsfollowing resection of the primary tumor shown in A shows a recurrent mass with similar signal characteristics andanatomic location. The recurrent mass is slightly larger in size and demonstrates an increase in lesion heterogeneity andmargin irregularity.

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MATERIALS AND METHODS

Both specimens were fixed in 10% buffered formalin,routinely processed, sectioned at 5 �m, and stained bythe hematoxylin and eosin method. Using the avidin bio-tin peroxidase complex method, antisera directed to thefollowing were applied: S-100 protein (Dako Corp,Carpinteria, CA, USA; polyclonal dilution 1:800), epi-thelial membrane antigen (Dako Corp; monolconal E29,

dilution 1:20), neurofilament protein (Dako Corp; mono-clonal 2F11, dilution 1:75), synaptophysin (ICN, CostaMesa, CA, USA; monoclonal 3SY8, dilution 1:40), des-min (Dako Corp; monoclonal DER11, dilution 1:100),MYO D1 (Dako Corp; monoclonal 5.8D, dilution 1:50),myogenin (Dako Corp; polyclonal, dilution 1:4000),pan-keratin (Zymed; South San Francisco, CA, USA;monoclonal AE1-AE3, dilution 1:200); low molecularweight keratin (Becton Dickinson, San Jose, CA, USA;

FIG. 3. The recurrent tumorwas composed entirely ofpoorly differentiated cells (A)with moderate to scant eosin-ophilic cytoplasm (B). A: he-matoxylin and eosin, originalmagnification ×160; B: hema-toxylin and eosin, originalmagnification ×400.

FIG. 2. (A) Histologically, theprimary tumor was in largepart a typical schwannoma.(B) At high magnification,nests of rhabdomyoblasticcells are seen to lie in a mu-coid stroma. A: hematoxylinand eosin, original magnifica-tion ×160; B: hematoxylin andeosin, original magnification×400.

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monoclonal CAM 5.2, dilution 1:50), and p53 (DakoCorp; monoclonal DO-7, dilution 1:200).

RESULTS

The primary tumor, particularly at low power magni-fication, showed all of the characteristic features ofschwannoma, including a thick collagenous capsule, anattenuated nerve fascicle on its surface, hyalinized ves-sels, an admixture of compact Antoni A tissue featuringthe formation of occasional nodules and Verocay bodies,as well as Antoni B tissue (Fig 2A). MIB-1 staining inthis component was essentially 0. At higher power (Fig.2B), cytologically malignant cells were present singlyand in loose clusters often accompanied by a somewhatmucoid matrix. Approximately 50% of this tumor com-ponent showed MIB-1 immunoreactivity. The cells var-ied from uninucleate to multinucleate, were hyperchro-matic and irregular in configuration, and featured fre-quent mitoses, some abnormal. Cytoplasm varied inquantity from scant to moderate, being pale to ampho-philic. Myotubes and cross-striations were not observed.The neoplastic Schwann cells of the schwannoma com-ponent showed strong uniform immunoreactivity forS-100 protein and membranous staining for collagen 4.Neurofilament protein immunoreactivity was limited tothe nerve fascicle on the tumor surface and to nervefibers within a minor portion of the tumor. Epithelialmembrane antigen staining was limited to perineurialcells of the fascicle and in the tumor capsule. Scatteredweak to moderately p53-immunoreactive nuclei werenoted within the Schwann cell component. Three myoidmarkers (desmin, myogenin, and MYO D1) showed no

reactivity within the Schwann cells; the same was true ofsynaptophysin, keratin (AE1 AE3; CAM5.2), and CD99.In contrast, the scattered cytologically malignant cellsshowed variable but strong reactivity for all three myoidmarkers, as well as for synaptophysin. No staining wasseen for CAM5.2, keratin (AE1-AE3), epithelial mem-brane antigen, S-100 protein, or CD99. p53 staining wasfrequently seen in the malignant cells and was moderateto marked in degree.

The recurrent tumor consisted entirely of malignantcells intermediate to small in size (Fig. 3A). Focally,these were seen to permeate a nerve. Their cytology var-ied from spindle to somewhat epithelioid (Fig. 3B) andoccasionally multinucleate. Myoid markers (desmin,myogenin, myoD1) showed strong reactivity in largepatches of neoplastic cells (Fig. 4A). Strong, but actuallyless widespread, synaptophysin staining was also noted(Fig. 4B). Scant CAM 5.2 and rare AE1–AE3-positivecells were seen, as was a single epithelial membraneantigen-reactive tumor cell. No recognizable epithelialstructures were noted. A CD99 stain was negative. p53immunoreactivity was moderate to strong in scatteredneoplastic cells. Approximately 75% of cells wereMIB-1 immunopositive. Ultrastructurally, the malignantcells included rhabdomyoblasts featuring thick and thinfilaments and Z-band formation (Fig. 5A) as well assmall, poorly differentiated, neuronal cells containingscant secretory granules (Fig. 5B).

DISCUSSION

Divergent differentiation, the very essence of normalembryologic development, is a genetically determined

FIG. 4. The recurrent tumorwas immunoreactive for bothmyoid markers, here seen asmyogenin staining (A) and forthe neuronal marker synapto-physin (B). A: original magni-fication ×100; B: original mag-nification ×160.

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process also seen in neoplasia. With reference to centralnervous system tumors, it manifests as a subtle shift indifferentiation to closely related cell types. Examples in-clude mixed glioma (oligoastrocytoma),14 tumors show-ing more substantial divergence, e.g., glioneuronal neo-plasms (ganglioglioma),12 and truly heterologous differ-entiation, such as gliomas exhibiting skeletal muscle,chondro-osseous, or even true epithelial differentiation.18

Similar transitions occur in peripheral nerve tumors, bothbenign and malignant. Benign examples include 1) ordi-nary neurofibromas in which perineurial-like cells ap-pear to arise from Schwann cells, which, based on recentgenetic evidence,20 appear to be the principle if not theonly neoplastic cell, and 2) rare examples of neurofi-broma with more obvious divergent differentiation. Thelatter include a vaginal neurofibroma containing benignskeletal muscle (benign Triton tumor),1 an example ofplexiform neurofibroma with extensive glandular differ-entiation,22 and angiosarcomas arising from neurofibro-mas.23 Far more often, the underlying lesion is anMPNST6 in which embryonal rhabdomyosarcoma is themost frequently occurring element (malignant Triton tu-mor).6,25,28 In approximately 15% of cases, the latter alsofeature other mesenchymal or even epithelial compo-nents (MPNST with pluridirectional differentiation).5

Among the other mesenchymal components are chondro-sarcoma, osteosarcoma, and even rare examples of an-giosarcomatous elements.23 Far less frequent thanMPNST with divergent mesenchymal differentiation areexamples in which epithelium of glandular, squamous, orneuroendocrine types are also present or occur alone(glandular MPNST).6,9,26,27 Interestingly, unlike the ma-

lignant mesenchymal tissues noted above, glandularcomponents are, with rare exception, benign in appear-ance.27 Of MPNSTs showing any form of divergent dif-ferentiation, an association with neurofibromatosis type1 is seen in the majority.6,27,28

Divergent differentiation in conventional schwanno-mas is a rare event.21 Osseous metaplasia is often con-sidered a secondary phenomenon superimposed upondystrophic calcification related to hyalinized vasculatureand tumor ischemia. Nonetheless, true osseous as well ascartilaginous, and even adipose, differentiation does oc-cur in schwannomas10,13,19; the latter is best seen as acomponent of psammomatous melanotic schwannoma inCarney complex.3 Melanin production as seen in mela-notic schwannomas, more often benign than malignant,is accepted as being within the repertoire of schwanniancells and is not considered divergent differentiation. Thesame is true of glial fibrillary acidic protein expression.17

Although once thought to be a manifestation of glandulardifferentiation,2,5,7,8,31 the finding of glands within su-perficially situated schwannomas is now attributed toentrapment of normal cutaneous adnexae (sweat glandsreplete with myoepithelial cells).27 Thus, the spectrum ofdifferentiation in schwannomas is largely limited to be-nign mesenchymal tissues. Those rare examples of an-giosarcoma supervening upon schwannoma23,24 arethought not to represent divergent differentiation. In-stead, it is considered a manifestation of intratumoralvascular stasis and malignant transformation of residentendothelial cells.24 This interpretation is supported inpart by the immunophenotypes of the two components,which differ entirely, and lack of transitional cells.23,24

FIG. 5. Ultrastructurally, therecurrent tumor consisted ofcells showing either rhabdo-myoblastic (A) or neuronal dif-ferentiation (B). This con-sisted of thick and thin fila-ments in association withZ-bands (A) and of sparseneurosecretory granules (B).A: or iginal magnif icat ion×12,000; B: original magnifi-cation ×18,000.

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Myoid differentiation has not heretofore been describedin schwannoma. The same is true of bona fide neuronaltransition to small cell differentiation. Although small“neuroectodermal” tumor has twice been reported,11,29

neither immunohistochemical (neuronal marker) stainingnor diagnostic ultrastructural features (processes, micro-tubules, secretory granules) have been documented. Ourcase illustrates both. Thus, the range of differentiation,which included scant true epithelium, is truly unique.

In that conventional schwannoma differs from neuro-fibroma and MPNST with their varied cytologic makeup,our case brings focus upon the well-differentiatedSchwann cell as the element undergoing the process ofdivergent differentiation. Reflecting back upon neurofi-broma, the lesion underlying over half of MPNST, it maybe that their so-called “perineurial-like cells” with fea-tures intermediate between Schwann and perineurialcells, having already undergone subtle divergent differ-entiation along perineurial lines, may be those prone toundergo further differentiation along mesenchymal andrarely glandular lines. Recent work has recognized thepotential of schwannoma cells to undergo anaplasia andto form malignant epithelioid cell tumors.29 Until now itwas thought that, unlike neurofibromas, the lack of re-ports of metaplasia to malignant mesenchymal tissues inschwannoma reflected a basic limitation of the metaplas-tic potential of highly differentiated Schwann cells com-prising this tumor. This would also explain why meta-plastic changes in MPNST are far more frequent in thosearising from neurofibromas or in patients with neurofi-bromatosis type 1 than in examples occurring de novo inperipheral nerves. Although the present case does notdisprove this explanation, it is remarkable because itshows that malignant mesenchymal metaplasia inschwannomas can occur. Furthermore, additional evi-dence is provided for the role of the neoplastic Schwanncell in the formation of heterologous malignant mesen-chymal and epithelial tissues in this major type of pe-ripheral nerve sheath tumor. �

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